Biomedicine & Pharmacotherapy 111 (2019) 765–777

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Emerging pathways to neurodegeneration: Dissecting the critical molecular T

mechanisms in Alzheimer’s disease, Parkinson’s disease
Sean Hong Tana, Venkatanaidu Karrib, Nicole Wuen Rong Taya, Kuan Hui Changa, Hui Yen Aha,
⁎
Phui Qi Nga, Hui San Hoa, Hsiao Wai Keha, Mayuren Candasamyc,
a
School of Pharmacy, International Medical University, No 126, Jalan Jalil Perkasa 19, Bukit Jalil 57000, Kuala Lumpur, Malaysia
b
Department of Toxicogenomics, Faculty of Health, Medicines, Life Sciences, Maastricht University, Maastricht, Netherlands
c
Department of Life Sciences, School of Pharmacy, International Medical University, No 126, Jalan Jalil Perkasa 19, Bukit Jalil 57000, Kuala Lumpur, Malaysia

A R T I C LE I N FO A B S T R A C T

Keywords: Neurodegenerative diseases are usually sporadic in nature and commonly influenced by a wide range of genetic,
Alzheimer’s disease life style and environmental factors. A unifying feature of Alzheimer’s disease (AD) and Parkinson’s disease (PD)
Parkinson’s disease is the abnormal accumulation and processing of mutant or damaged intra and extracellular proteins; this leads to
Ubiquitin proteasome neuronal vulnerability and dysfunction in the brain. Through a detailed review of ubiquitin proteasome, mRNA
mRNA splicing
splicing, mitochondrial dysfunction, and oxidative stress pathway interrelation on neurodegeneration can im-
Mitochondrial dysfunction
Oxidative stress
prove the understanding of the disease mechanism. The identified pathways common to AD and PD nominate
Biomarker promising new targets for further studies, and as well as biomarkers. These insights suggested would likely
provide major stimuli for developing unified treatment approaches to combat neurodegeneration. More broadly,
pathways can serve as vehicles for integrating findings from diverse studies of neurodegeneration. The evidence
examined in this review provides a brief overview of the current literature on significant pathways in promoting
in AD, PD. Additionally, these insights suggest that biomarkers and treatment strategies may require simulta-
neous targeting of multiple components.

1. Introduction
Neurodegeneration is described as the loss of specific type of neu-
rons, pattern and distribution of the neurons, leading to central nervous
system (CNS) dysfunction progressively and often untreatable [1,2].
Neurodegenerative diseases include a variety of pathological patterns
and clinical presentations, such as Alzheimer’s disease (AD), Parkinson
disease (PD), Progressive supranuclear palsy (PSP) and dementia with
Lewy bodies (DLB) [3]. Among these diseases, AD and PD are the most
prevalent neurodegenerative diseases where AD is known as an esca-
lating dementia, while PD is primarily characterized as a movement
disorder.
The prevalence of AD has elevated to an estimated 40 million pa-
tients globally [4]. AD running in the family, known as familial AD,

Abbreviations: %OH, hydroxyl radicals hydroxyl radicals; 4-HNE, 4-hydroxynonenal; AD, Alzheimer’s disease; APOE- ε4, εε4 allele of apolipoprotein; APP, amyloid
precursor protein; ARJP, autosomal recessive juvenile parkinsonism; AS, alternative splicing; ATP, adenosine triphosphate; ATP13A2, adenosine triphosphatase
13A2; Aβ, beta-amyloid; BACE, beta-secretase; Ca2+, calcium; CNS, central nervous system; DJ-1, protein deglycase 1; Drp1, dynamin-related protein 1; E1, ubiquitin
activating; E2, ubiquitin conjugating; E3, ubiquitin ligating; ER-α, estrogen receptor-α; ETC, electron transport chain; FBP1, far upstream sequence element-binding
protein 1; FBXO7, F-box protein 7; Fis1, mitochondrial fission protein 1; GABA B, γ-aminobutyric acid B; GBA1, glucocerebrosidase 1; GFAP, glial fibrillary acidic
protein; GPCR51, G-protein-coupled receptor 51; GSH, glutathione; H2O2, hydrogen peroxide; HT, Huntington’s disease; KGDHC, alpha-ketoglutarate dehydrogenase
complex; LB, Lewy body; LRRK2, leucine-rich repeat kinase 2; MAO-A, monoamine oxidase-A; MAO-B, monoamine oxidase-B; MAPT, microtubule associated protein
tau; MDA, malondialdehyde; Mfn1, Mitofusins 1; Mfn2, Mitofusins 2; mRNA, messenger ribonucleic acid; O2−, superoxide; OMM, outer membrane of mitochondria;
Opa1, optic atrophy protein 1; Pael-R, Parkin-associated endothelin-like receptor; PARK2, Parkinson disease protein 2; PARK6, Parkinson disease protein 6; PARK7,
Parkinson disease protein 7; PD, Parkinson’s disease; PINK1, PTEN-induced putative kinase 1; PKC, protein kinase C; PLA2G6, phospholipase A2G6; PRKN, Parkin;
PS1, presenilin 1; PS2, presenilin 2; PSP, progressive supranuclear palsy; PTP, permeability transition pore; RAGE, receptor for advanced glycation products; ROS,
reactive oxygen species; SNCA, alpha-synuclein; SNCAIP, synuclein alpha interacting protein; SNPC, substantia nigra pars compacta; SOD, superoxide dismutase;
SRRM2, serine/arginine repetitive matrix 2; TFAM, transcription factor A, mitochondrial; TRX, thioredoxin; TV12, transcript variant 12; TV3, transcript variant 3;
UCH-L1, ubiquitin carboxy-terminal hydrolase L1; UPS, ubiquitin proteasome system; VDACs, voltage-dependent anions channels
⁎
Corresponding author.
E-mail address: mayurencandasamy@imu.edu.my (M. Candasamy).

https://doi.org/10.1016/j.biopha.2018.12.101
Received 13 October 2018; Received in revised form 18 December 2018; Accepted 23 December 2018
0753-3322/ © 2018 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
S.H. Tan et al.
represents less than 5% of AD cases; whereas the mostly seen AD,
known as sporadic AD occupies for more than 90% of AD cases [5].
Although genetic mutation can be one of the causative factors of AD,
most studies have proposed that the interaction between lifestyle and
environmental factors can also lead to AD [1]. The irreversible brain
damage in AD progresses slowly and eventually impairs the memory,
perception and behaviour [6]. For instance, patients with advanced AD
shows verbal episodic memory and behavioural troubles [7]. Also, the
presence of intracellular neurofibrillary tangles and extracellular
neuritic plaques are the key pathological features of AD [8]. Since
molecular studies of AD began in the early 1980s, many scientists and
healthcare professionals have delved into all aspects of this complex,
multifactorial syndrome [4]. The most prevalent hypothesis is the beta-
amyloid (Aβ) cascade theory. This theory hypothesised that increased
production of insoluble extracellular Aβ leads to Aβ aggregation and
deposition manifesting as plaques in the brain. The plaques are believed
leads to dementia and eventually death [9]. The theory holds that an
amyloid-related mechanism that prunes neuronal connections in the
brain in the fast-growth phase of early life may be triggered by ageing-
related processes in later life to cause the neuronal withering of AD. The
ongoing aggregation of Aβ which occurred due to alternations of sig-
nalling-protein such as glycogen synthase kinase-3β, fyn kinase and
cyclin-dependent kinase (CDK5) could lead to Aβ oligomers formation,
Aβ1-42 particularly neurotoxic when aggregated in the brain [10]. The
second one is tau hypothesis, in this theory, hyperphosphorylated tau
begins to pair with other threads of tau. Eventually, they form neuro-
fibrillary tangles inside nerve cell bodies destroys the neurons [11]. On
the other hand, the mutation in APP, tau, presenillin-1, presenillin-2
and ApoE4 are involved in aggregation of Aβ as well [12]. The for-
mation of Aβ oligomers alter the signalling pathways and glutamate
receptors, as a result, neurogenesis defect and synaptic loss happened in
neurons which produce glutamate or acetylcholine as neurotransmitters
[13].
PD is the second most common neurodegenerative disorder after
Alzheimer’s disease. Parkinson disease typically develops between the
ages of 55 and 65 years and occurs in 2% of people over the age of 60
years, rising to 3.5% at age 85–89 years [14]. It is a complex disorder,
described by the loss of dopamine producing neurons in substantia
nigra pars compacta (SNPC) as well as the presence of Lewy bodies in
the SNPC and locus coeruleus leading to poor motor control [1,15]. The
evidences on dementia with Lewy bodies (DLB) and PD as two syn-
dromes within the same disease spectrum. Both are pathologically
characterized by neuronal loss and Lewy bodies, consisting of inclu-
sions of α-synuclein [16].
PD is caused by deterioration of the dopaminergic neurons in the
extrapyramidal tract of the midbrain. There is also accumulation of α-
synuclein proteins, known as Lewy bodies, in the central, autonomic,
and peripheral nervous system as the hallmarks of the PD [17]. The
intracellular aggregated α-synuclein makes a hole in the neuronal
membrane killing neuronal through oxidative stress, excitotoxicity,
energy failure and neuroinflammation [18]. Thus, PD patients are
presented with clinical manifestations such as resting tremor, muscle
rigidity, postural instability, bradykinesia and a mask-like facial ex-
pression [19]. They cannot perform well in sequence learning, motor
sequence and switching between different tasks as well as verbal flu-
ency [20]. Alike with AD, 90 to 95% of the PD cases are sporadic PD,
whereas 5 to 10% of cases are familial PD [21]. The neuropathology of
PD is poorly understood until it has been considered as the prototypical
nongenetic disorder [13]. Gene mutations in alpha-synuclein (SNCA),
parkin (PRKN), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1),
PTEN-induced kinase 1 (PINK1) and protein deglycase 1 (DJ-1) genes
are associated with PD as they result from the impairment of the bio-
logical pathways such as the ubiquitin proteasome system (UPS) and
mitochondrial dysfunction [22,23].
Several studies suggest that DLB, PD and AD overlap in term of
memory impairment. One clinical data reported memory changes as
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Biomedicine & Pharmacotherapy 111 (2019) 765–777
first cognitive complaint by DLB, PDD and AD patients [24]. On the
other hand, dementia, cognitive fluctuations and visual hallucinations
are common clinical features found in both DLB and PD. Others im-
portant clinical presentation for both DLB and PD include executive
dysfunctions and visual-spatial abnormalities [25]. DLB and PD dif-
ferent as bradykinesia and rigidity are more common in DLB [26]. DLB
presented with greater deficiencies of attention while in PD it is less
common [27]. However, executive functions and visual symptoms are
claimed to be more impaired in PD compared to DLB probably due to
reduce metabolism in visual pathways in PD [28,29]. In DLB, halluci-
nations occur spontaneously, which is reported to be related to Lewy
Bodies in temporal lobe of brains [30], while hallucinations in PD often
occur after dopaminergic therapy [25,31]. There is report claimed that
rate of cognitive decline is faster in DLB compared to PD and AD
[32,33]. Clinical data reported psychiatric symptoms especially delu-
sions are more common in DLB compared to PD and AD [24].
However, this review mainly focuses on two of the most common
neurodegenerative diseases, AD and PD as they share some common
clinical pathological and epidemiological features. Thus, the objective
is to improve the understanding of the role of critical biological path-
ways such as UPS, aberrant alternative splicing, mitochondrial dys-
function and oxidative stress impact in AD, PD.
2. Factors that contribute to the development of the
neurodegenerative diseases
The development of neurodegenerative diseases may result from a
number of factors: aging, genetics and environmental factors (Fig. 1).
2.1. Aging
Ageing is a major risk factor of neurodegenerative diseases. Ageing
not only makes patients more prone to neurodegenerative diseases, but
also impairs their abilities of self-repair. The rising incidence of age-
related neurodegenerative diseases has become an important health
concern in the world. Aging is associated with functional impairments
such as dementia and motor neuron disability in neurodegenerative
diseases such as AD and PD [34]. In the cellular level, ageing is asso-
ciated with accumulating oxidative stress, declining mitochondrial
function, impaired DNA repair and decreased tissue regeneration take
part in the development of AD and PD [35]. However, the increase of
free radicals in the brain is not caused by elevation of oxidative stress.
Studies shown that the activities of superoxide dismutase (SOD), cata-
lase, glutathione peroxidase and glutathione reductase were reduced in
affected brain regions in AD, PD [36]. As mitochondrial efficiency de-
clines with age, a number of observations have led researchers to
speculate that mitochondrial dysfunction may contribute to the for-
mation of misfolded protein aggregates and subsequently lead to AD
and PD [37,38].
Fig. 1. Factors contributing to the development of AD and PD.
S.H. Tan et al. Biomedicine & Pharmacotherapy 111 (2019) 765–777

Table 1
Proteins that have a function in major neurodegenerative diseases.
Disease Genetic Causes Inheritance Pathogenesis References

AD APP Dominant Give rise to Aβ formation, the primary senile plaque. [49]
PS1 and PS2 Dominant Increased Aβ42/Aβ40 ratio. [50]
PD α-synuclein Dominant Genetic polymorphisms in the gene increases tendency to form Lewy bodies. [51]
LRRK2 Dominant A kinase. Function unknown. [52,53]
PARKIN Recessive Mutation in the gene causes impaired protein degradation. [45]
PINK1 Recessive A kinase localised to mitochondria. Function unknown. Seems to protect against cell death. [47]
DJ-1 Recessive Protects the cell against oxidant- induced cell death. [46]

2.2. Genetics
Family studies have established that genetic factors play a crucial
role in AD, especially in younger onset cases (< 65 years) [39]. Familial
forms of AD follow an autosomal dominant inheritance pattern which
result from mutations in three genes (APP, presenilin-1, and presenilin-
2) that are responsible for Aβ plaque formation (Table 1). Non-familial
AD/ sporadic AD typically occurs at the age of 65 years or older, ac-
counting for most of the cases of AD [40]. It has been associated most
consistently with ε4 allele of apolipoprotein (APOE- ε4) gene which is a
very low-density lipoprotein carrier required for APOE- ε4 deposition
[41]. Carriers of the APOE- ε4 allele have reduced AD ages at onset,
with 3-fold and 15-fold risk excesses observed in heterozygotes and
homozygotes respectively [42]. The vast majority of AD is sporadic,
with no obvious genetic component, suggesting that other mechanisms
are responsible.
Specific causal mutations appear to be more prominent in early-
onset PD which affect at least five genetic loci (Table 1). The initial
discoveries were mutations of the gene encoding SNCA protein which
have been related to early-onset of PD [43]. Mutations in leucine-rich
repeat kinase 2 (LRRK2) gene have been associated with late-onset PD
which may also contribute to non-familial PD [44]. Identified muta-
tions in other genes include Parkinson disease protein 2 (PARKIN or
PARK2), PTEN-induced putative kinase 1 (PINK1 or PARK6) and DJ-1
(PARK7), all of which follow a recessive inheritance mode [45–47].
Since 90% of PD cases are sporadic and cannot be attributed to only
genetic factors, this suggests that PD has a multifactorial aetiology [48].
2.3. Environmental factors
It is known that the aetiology of PD, AD is multifactorial (Table 2),
and there is evidence that potential external factors including lifestyle
and chemical exposures are linked with the risk of the onset of these
diseases. Environmental factors such heavy metals, pesticides have
been involved in PD, AD development due to their ability to disrupt the
neuronal functions [54,55]. Much ongoing research is focusing on
metals exposure as potential risk factors for neurodegenerative diseases.
Although a direct casual role for some metals such as lead (Pb) alu-
minium (Al), iron (Fe), copper (Cu), zinc (Zn), mercury (Mg), arsenic
(As), and cadmium (Cd) has not yet been definitively demonstrated,
epidemiological evidence suggests that increased levels of these metals
in the brain may link to the development and progression of AD and PD
[8,56]. Exposure to toxic heavy metals such as Pb, MeHg, Cd, and As
has been documented to cause neurotoxicity which eventually leads to
neurodegenerative diseases [57].
3. The possible underlying molecular mechanisms in AD, PD
neurodegeneration
Relatively little is known regarding the mechanisms of AD and PD
pathogenesis. It has been suggested that impairments of UPS, dysre-
gulation in alternative splicing, mitochondrial dysfunction [69], and
decreased protection against oxidative stress and apoptosis have fun-
damental roles in neurodegenerative diseases such as AD and PD. These
defects are normally resulting from genetic, environmental risk factors
[70].
4. The role of the ubiquitin-proteasome system (UPS) in
neurodegenerative diseases
UPS is a mechanism for protein degradation. It plays an important
role in regulating wide variety of cellular function [71]. The UPS is
essential for the non-lysosomal degradation and clearance of short-
lived, misfolded, mutant, and damaged proteins in eukaryotic cells.
Structural and functional deficits in the 26S and 20S proteasomes may
lead to AD, and PD [72].
4.1. Alzheimer’s disease
Many evidences proposed that AD might due to defect in UPS
function (Fig. 2). Evidence suggested that there are increased amount of
misfolded and aggregated protein accumulates in specific structure in
AD, such as plaques and tangles [73]. Also, certain amount of ubiquitin
mutant proteins are shown in plaques and tangles which could be the
mediator of Aβ-induced neurotoxicity [74]. Aggregated oxidized pro-
teins in brain with AD could further reduce proteasome activity, which
is responsible to destroy damaged proteins [73,75].
Reported studies showed that the relationship between Aβ and
proteasome pathway, where the accumulation of Aβ could diminish
proteasome function [75]. The balance between Aβ production and
degradation play a crucial role in the accumulation of Aβ in neurons, it
indicates UPS is needed for Aβ metabolite clearance [76–78]. For in-
stance, both Aβ40 and Aβ42 oligomers affect proteasome activity by
notably reducing the chymotrypsin-like activity, trypsin-like activity

Table 2
Some of the proposed environmental factors for the major neurodegenerative diseases.
Environmental Factor(s) Associated With References

AD
• Metals (Pb, Hg, As, Cd, Al, Fe, Cu, Zn) Increased risk, inconclusive results [54,55,58,59]
• Pesticides, Solvents, Electromagnetic fields Increased risk, inconclusive results [60]
•
PD
Traumatic brain injuries, Infections, Inflammations Increased risk [61]

• Metals (Pb, As, Hg, Cd, Al, Fe, Cu, Zn) Increased risk [62,63,64,65]
• Pesticides, Herbicides Increased risk [66,67]
• Head injuries with loss of consciousness Increased risk [66,68]

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S.H. Tan et al.
Fig. 2. The defective UPS increases the accumulation of ubiquitin conjugates,
and eventually tau as well as β-amyloid peptide, both of which are the hall-
marks of AD.
and the peptidyl glutamyl-like activity of the proteasome [79]. Other
than that, E2-25 K/Hip2, an ubiquitin-conjugation enzyme, is reported
to mediate Aβ neurotoxicity due to its enzymatic activity in the in-
hibition of proteasome [80]. Furthermore, impairment in tau turnover
results in AD since tau can be degraded by proteasome [81]. It is sug-
gested that the proteasomal dysfunction in AD occurs when tau-paired
helical filament is prevented from binding with proteasome [82].
More evidences have shown that defects in UPS may lead to AD. For
instance, normal aging process reduces proteasome activity that may
leads to accumulation of Aβ and tau [83]. Also, accumulation of Aβ and
tau will reduce the proteasome activity which then causes even more
accumulation of Aβ and tau. This is a vicious cycle where aggregated
Aβ and tau keeps increasing thus, causing AD to be more severe.
4.2. Parkinson’s disease
Growing evidence shows that defective UPS causes PD (Fig. 3).
Under normal condition, cellular proteins undergo a series of reaction
in UPS before degradation [79]. With impairment of UPS, the non-
functional intracellular proteins accumulate in the brain, resulting in
damaged dopaminergic neurons and causing PD [84]. The enzymes
responsible for tagging prior non-functional intracellular protein de-
graded by proteasome include ubiquitin activating (E1), ubiquitin
conjugating (E2) and ubiquitin ligating (E3) enzymes [79]. Studies have
showed that genetic mutation in PARKIN (E3), SNCA and UCH-L1, a
member of deubiquitinating enzyme could disrupt UPS and lead to
aggregation of protein substrate which is harmful to the survival of
neuron [85].
Fig. 3. The schematic representation of mutated Parkin, UCH-L1 and SNCA
genes contribute to defective UPS and the assemble of these non-functional
intracellular proteins triggers the development of PD.
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Biomedicine & Pharmacotherapy 111 (2019) 765–777
In an in-vitro investigation, mutated PARKIN is unable to function as
E3 enzyme and non-functional cellular protein is unable to be tagged
and degraded [86]. Hence, mutation in PARKIN may directly affects the
survival of dopaminergic neuron, leading to PD. Other than that, the
ability of mutated PARKIN to change the solubility of non-functional
protein is found and this encourages accumulation of PARKIN substrate
such as parkin-associated endothelin-like receptor (Pael-R), cell divi-
sion control-related protein (CDCrel 1 and 2a), far upstream sequence
element-binding protein 1 (FBP1), cyclin E and p38 (JTV-1/AIMP2)
[87,88]. This is due to large number of PARKIN substrates are presented
in the brain of PD patient with PARKIN mutation [89]. These accu-
mulated PARKIN substrates alter the normal function of neuronal cell
and result in the development of PD [88].
Evidence also showed that mutation or triplication of Lewy bodies
which is SNCA gene could cause PD [87]. Impairment in clearance of
SNCA due to mutated SNCA gene results in excessive SNCA accumu-
lation in the brain [90]. These aggregated SNCA further reduces the
proteasome activity, causing development of PD [87]. Based on these
evidences, there is a direct connection between abnormal SNCA ag-
gregation and dopaminergic neuronal cell death.
UCH-L1 which is crucial for the proteasome function, is found
mutated in PD [91]. The ubiquitin hydrolase activity of mutated UCH-
L1 is noticeably reduced in an in-vitro study, proving that decrease in
polyubiquitin hydrolysis can cause dopaminergic neuronal death [92].
Other than this, aging and exogenous stress also encourage aberration
of UPS and subsequently contribute to PD pathogenesis [93].
5. Aberrant alternative splicing events in neurodegenerative
diseases
Aberrant alternative splicing plays a significant role in neurode-
generative diseases, particularly in AD and PD [94,95]. Primary tran-
script of pre-mRNA undergoes removal of introns and simultaneous
formations of varying combinations of exon regions, also known as
alternative splicing (AS) [95]. AS is one of the most important me-
chanisms to synthesis a large number of mRNA and protein isoforms
from the low number of human genes [96]. It is a widespread gene
regulatory process by which exons of primary transcripts (pre-mRNAs)
are spliced into different arrangements to produce structurally distinct
mRNA variants [97]. This mechanism of gene product plays a critical
role in cell function [98]. It is estimated that more than 75% of genes in
the human genome are alternatively spliced in CNS [99]. Dysregulation
of AS has been linked to the number of human diseases including
neurodegenerative diseases [100].
5.1. Alzheimer’s disease
AD is associated with the dysregulation of several proteins that
stems from aberrant alternative splicing. One such protein is tau, which
is well-known as one of the major contributors to the pathophysiology
of AD. In the human brain, six isoforms of protein tau has been iden-
tified and differs by the inclusion or exclusion of exon 2, 3 and 10
[101]. Disruption of the splicing process involving exon 10 is sufficient
to cause disease of the tau protein [102]. The β-secretase (BACE) and γ-
secretase drives two subsequent enzymatic digestions that forms Aβ.
The exon 3 and 4 of BACE1 have complex splicing profiles and the rich
sequence of G in exon 3 increases the generation of full-length BACE
[103,104]. Familial AD is mostly associated with mutations in genes
encoding presenilin 1 (PS1) and presenilin 2 (PS2) which are integral
membrane proteins. Deletion of exon 9 in PS1 disrupts the structure and
leaves out an important residue, D257 [105]. Exon 4 of PS1 has two 5′
splice sites resulting in two splice variants that differ by four amino
acids, VRSQ, which forms a potential site for protein kinase C (PKC)
phosphorylation. Rodents only have the longer PS1 isoform, resulting in
a more readily regulated PS1 protein, thus generating less Aβ [106]. In
PS2, deletion of exon 5 expresses truncated PS2 isoform, PS2V which
S.H. Tan et al.
accumulates rapidly in the hippocampus of patients with sporadic AD.
This is due to the overexpression of high-mobility group A protein 1a
(HMGA1a), a sequence-specific RNA-binding factor [107]. Another
protein of interest in AD is GFAP (glial fibrillary acidic protein), its
variant, GFAP + 1 was found in AD brains due to the expression of two
novel splice forms: lacking exon 6 or deletion of 164 nt [108]. Neurons
in the hippocampus that failed to degrade aberrant protein result in
their accumulation, which may lead to neuronal death [109].
The splicing process influence the gender specific AD progress
[110]. Hypothetically, this may be due to the alterations in the ratio of
canonically and alternatively spliced isoforms of the estrogen receptor-
α (ER-α) [111]. The most common ER-α isoform found in the brain is
without exon 7. Complete or partial exclusion of this exon is also as-
sociated with double, triple, or multiple exon skipping variants [112].
In AD brain, more wild type ER-α is found rather than the alternatively
spliced isoforms. Another dominant negative variant, isoforms ex-
cluding exon 2, was also found to be reduced in AD brain, particularly
in women. Overexpression of dominant splice variant del. 7 may de-
crease the effect of estrogen on cognitive function [113]. Another gene
that may be implicated in AD is receptor for advanced glycation pro-
ducts (RAGE). Its alternatively spliced form, sRAGE is expressed with a
lower level in AD and may disrupt the normal regulation of RAGE
signalling which could lead to abnormal structure of extracellular do-
mains [114]. 17 A, a non-coding RNA found in intron 3 of the G-pro-
tein-coupled receptor 51 gene (GPCR51) regulates the alternative
splicing of the gene, as well as its pre-mRNA maturation. High levels of
17 A was found in AD brain may upregulate the ratio of Aβ production,
and a change in the spliced variant ratio of GPCR which could impair
normal γ-aminobutyric acid B (GABA B) signalling [115].
5.2. Parkinson’s disease
As of now, the aberrant alternative splicing of six genes have been
associated with PD: leucine-rich repeat kinase 2 (LRRK2), parkin 2
(PARK2), synuclein alpha interacting protein (SNCAIP), SNCA, micro-
tubule associated protein tau (MAPT), and serine/arginine repetitive
matrix 2 (SRRM2) [95]. The first gene identified in the pathophysiology
of PD is SNCA which encodes for SNCA, a protein found in the pre-
synaptic region [116]. SNCA has many functions and studies have
shown that the lack of its acidic C-terminus, specifically the exon 5 of
the 3′ region (SNCA112), impairs normal physiological function and
enhances aggregation of protein [117–120]. Dopaminergic neuron cell
death is promoted by the overexpression of SNCA112 [95]. Another
strong candidate gene for PD is SRRM2 encoding SR repetitive matrix 2
which has two main splice variants that differ at their 3′ region: the full
length SRRM2 and the shorter SRRM2 transcript that lacks exons 12-15.
In PD, SRRM2 switches from the basal transcript level to low levels of
the longer isoform and higher levels of the shorter isoform. It was found
out that the downregulation of the longer isoform is due to the corre-
sponding dysregulation of downstream exons and upstream exons
[121].
Tau protein is encoded by MAPT which plays a significant role in
the morphogenesis of axons, polarity of axons, and axonal transport
[122]. Tau mutations that enhance the inclusion of exon 10 by exerting
its effect on three cis-acting regulatory elements, induce overproduction
of 4R tau which may lead to tau pathology [95,123,124].
Mutations in the LRRK2 encoding for dardarin are the most common
cause of apparent sporadic PD and familial late-onset parkinsonism
[125]. LRRK2 acts indirectly by phosphorylating heterogeneous nuclear
ribonucleoproteins (hnRNP) which interact with basal splicing com-
plex, causing aberrant splicing variants [117]. The deletion of a 4-bp
intron at the splice donor site of exon 19 has been observed to impair
normal splicing [126]. The reported study showed that LRRK2
(G2019S) mutant cDNA causes the increased inclusion of exon 10 of
MAPT gene [119]. High levels of wild type LRRK2 gene influences the
expression of SNCA gene and gives rise to dysfunction in SNCA gene,
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Biomedicine & Pharmacotherapy 111 (2019) 765–777
resulting in the inhibition of proteasomal function and formation of
aggregates in neurons [117].
Autosomal recessive juvenile parkinsonism (ARJP) is associated
with mutations in the PARK2 encoding for PARKIN. PARKIN plays a
role in the ubiquitin proteasome system and is expressed in many re-
gions of the brain [95]. The change in the expression of the seven
isoforms derived from PARK2 results in Lewy body (LB) disease [127].
In PD, transcript variant 3 (TV3) which lacks of exons 3–5, and tran-
script variant 12 (TV12) which lacks of exons 2–7, were found to be
increased [128]. The pathogenic mechanism of ARJP may be attributed
to the structural variations of the PARK2 alternatively spliced isoforms.
There was a study reporting that E4SV, an alternatively spliced variant
of parkin that lacks exon 4 was increasingly expressed in sporadic PD
and it has completely lost its enzymatic activity [129].
SNCAIP gene which encodes synphilin-1 generates at least eight
spliced variants. Two of the variants produces isoforms synphilin-1 A
and synphilin-1B which are upregulated in PD [82]. Synphilin-1 A lacks
of exon 3 and 4 and includes exon 9 A. Its overexpression may con-
tribute to neurodegeneration via promotion of aggregation and sa-
turation of the ubiquitin proteasome system [95,128,130]. Autosomal
recessive early-onset parkinsonism is also tied to the aberrant alter-
native splicing in PTEN-induced putative kinase 1 (PINK1) gene. The
aberrant mRNAs are produced by a 23-bp deletion which disrupts the
acceptor site of exon 7 [131]. In addition, complete deletion of exon 7
and a novel U1-dependent splice-site mutation in exon 7 was found in a
Spanish family with PD members [132].
Other genes minorly associated with PD is protein deglycase DJ-1
(PARK7), adenosine triphosphatase 13A2 (ATP13A2), phospholipase
A2G6 (PLA2G6) and F-box protein 7 (FBXO7) [133]. Mutations in
PARK7 is linked to autosomal recessive parkinsonism [134,135],
whereby the alteration in the abundance of PARK7 splice variants are
found in PD brains and could act as potential biomarkers of the disease.
The skipping of exon 13 in ATP13A2 cause the deletion of the third
transmembrane domain [136] which may contribute to levodopa-re-
sponsive inherited atypical parkinsonism [137]. Abnormal mRNA
splicing of PLA2G6 is caused by a nucleotide mutation in exon 7 of the
gene. This causes a 4-bp deletion in its transcript, a change in the frame
shift in leukocytes [138]. Parkinsonism pyramidal disease is caused by
mutations in FBX07 in which the invariable splice donor of intron 7 is
removed [133,139,140].
6. Impact of mitochondria dysfunction in neurodegenerative
diseases
There is overwhelming evidence of impaired mitochondrial function
as a causative factor in AD, PD. More recently, evidence has emerged
for impaired mitochondrial dynamics in AD, PD neurodegenerative
diseases. Here, we provide a concise overview of the major findings in
recent years highlighting the importance of mitochondria in AD, PD.
6.1. Alzheimer's disease
Mitochondria have crucial role in brain function. They provide en-
ergy in the form of adenosine triphosphate (ATP) for brain cells and
allow communication between brain cells [141]. It has been proposed
that in sporadic AD mitochondrial dysfunction is the primary event that
causes Aβ deposition, synaptic degeneration, and formation of neuro-
fibrillary tangles [142]. In AD patients, mitochondrial dysfunction is
possible by different aspects including mitochondrial morphology or
mitochondrial dynamic, mitochondrial bioenergetics as well as mi-
tochondrial transport (Fig. 4).
6.1.1. Mitochondrial morphology or mitochondrial dynamic
Aβ peptide affects mitochondrial fusion and fission cycle. Fission
cycle of mitochondria allows damaged mitochondria to reduce their
size so it is easily selected through autophagy process [87]. On the
S.H. Tan et al.
Fig. 4. Disrupted mitochondria especially in terms of their morphology, bioe-
nergetics and transport contribute to the risk of AD.
other hand, fusion cycle allows mitochondrial enzymes and metabolites
to be distributed evenly throughout the mitochondria compartments.
Fusion cycle can also slow down the aging process of mitochondria
[75]. Dynamin-related protein 1 (Drp1) and mitochondrial fission
protein 1 (Fis1) are involved in fission cycle, while optic atrophy pro-
tein (Opa1) and Mitofusins 1 and 2 (Mfn1 and Mfn2) are involved in
fusion cycle [143]. Aβ peptide can enhance mitochondria fission and
reduce mitochondria fusion by affecting the expression of genes [143].
Therefore, like mitochondrial fusion, fission seems to be required to
maintain mitochondrial function in the brain. Trimmer and Borland
(2005) analysed the AD patients brain samples and found the changes
in mitochondrial morphology [144]. Another study on M17 neuro-
blastoma cell line with wild-type and Swedish mutant APP (over-
expressed) concluded that cells with Swedish mutant APP showed mi-
tochondrial morphology changes from thin and elongated to
fragmented and punctiform mitochondria [145]. When these protective
mechanisms fail, mitochondrial fission can also promote apoptosis, cell
death.
6.1.2. Mitochondrial bioenergetics
Electron transport chain (ETC) in mitochondria is responsible for
the production of ATP besides producing antioxidants to prevent neu-
ronal injury [146]. The affected electron transport chain influences the
ATP production and antioxidants expression, however, for synaptic
transmission in brain, high levels of ATP are required [147]. Low level
of ATP also matches the evidence that energy deficiency in brain is the
fundamental characteristic in AD [148]. Low level of ATP also matches
the evidence that energy deficiency in brain is the fundamental char-
acteristic in AD [148].
Aβ peptide induces reactive oxygen species (ROS) elevation by
causing dysfunction in complex I of electron transport system in mi-
tochondria. When complex I is blocked, amount of ATP reduced,
however amount of ROS increased as higher proportion of oxygen is
converted into free radicals [149]. As mitochondria are susceptible to
high ROS levels, they are attacked by ROS which eventually results in
mitochondrial membrane potential loss and leads to further ROS in-
crease [145,150]. Increased ROS levels and reduced ATP production in
mitochondria ETC pathway leads to AD. This is supported by a study
that involved mitochondria preparations from several AD mice models
which revealed a decreased in ATP production and excessive high ROS
levels [151].
6.1.3. Mitochondrial transport
Movement of mitochondria is important for maintaining normal
neuronal polarity and synaptic functions such as synaptic potential,
synaptic transmission and synaptic plasticity. Obstruction in mi-
tochondrial movement can affect communication between neuronal
cells through synaptic [87,88]. Kinesin is responsible to move mi-
tochondria in anterograde direction towards the nerve terminal while
dynein moves mitochondria in retrograde direction towards soma
[152]. A study carried out by Calkins et al. in mouse hippocampal
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Biomedicine & Pharmacotherapy 111 (2019) 765–777
neurons showed a notable decrease in anterograde movement of mi-
tochondria [153]. Therefore, mitochondrial fusion and fission defects
(Section 6.1.1) secondarily impair motility, and conversely, transport
defects affect mitochondrial morphology in neurons. However, the
mechanisms underlying this interplay remain to be determined. An
ultrastructural study concluded that there is a loss in normal micro
tubular structure around intracellular Aβ peptide, where this reduction
could lead to impaired mitochondria movement inside neurons [154].
6.2. Parkinson’s disease
PD is described by several characteristics, one of which is mi-
tochondrial dysfunction. Over the last few years, evidence has accu-
mulated that mitochondrial dysfunction is strongly associated with PD.
Several mutants are known to contribute to abnormal mitochondrial
function, one of which is the mutated SNCA [155]. The accumulation of
insoluble cytoplasmic proteins known as Lewy bodies in neurons is one
the major characteristics that contribute to PD. SNCA protein is closely
associated with disruption of mitochondrial function in PD by attaching
onto mitochondrial membrane and damaging the protein transport
system [156]. In other words, the destructions caused by SNCA is not
only limited to mitochondrial protein transport but also other mi-
tochondrial functions due to its localization on outer membrane [157].
When the genes in mitochondria undergo mutation, the normal
homeostasis of mitochondria is interfered, which further leads to neu-
ronal toxicity, loss of dopamine neurons and eventually PD. A recent
study using a transcription factor A, mitochondrial (TFAM) knockout
mouse model-induced mitochondrial dysfunction has shown depletion
in dopaminergic neurons [158]. Other than TFAM, two other genes
discovered in recent studies have demonstrated relationship with mi-
tochondrial dysfunction in familial PD, known as PARKIN and PINK1
[159] (Fig. 5). These two genes are the critical elements for the quality
control of mitochondria [160]. Moreover, there is evidence for a direct
involvement of PINK1 and PARKIN in abnormal mitochondrial dy-
namics in PD models [161,162]. When mitochondria is damaged, mi-
tochondrial depolarization arises when PINK1 selectively accumulate
on outer membrane of mitochondria (OMM) [163]. PINK1 accumulated
on OMM phosphorylates Parkin and ubiquitin which then leads to the
exposure of Parkin ubiquitin ligase activity [164]. The activation of
Parkin causes further damage to OMM proteins and stimulates ubi-
quitination [165]. At the same time, the affected mitochondria migrate
to the perinuclear region and undergo formation of mito-aggresomes by
mitophagy pathway [164].
However, in the neurons, PINK1 and PARKIN trigger the degen-
eration of the motor adaptor protein Miro, so the movement of the
damaged mitochondria along the axon of neuron may be inhibited
[166]. Eventually, the mitochondria stop at distal ends of neurons and
they are blocked from clearance due to the PINK1/Parkin-mediated
pathway [158]. Also, insufficiency of PINK1 proteins is the causative
factor of Ca2+ accumulation in mitochondria which subsequently leads
to the production of ROS and cell apoptosis in PD. The dysfunctional
mitochondria will lead to decreased membrane potential as well as low
ATP production. The mitochondria may become more susceptible upon
the exposure to toxins. Studies have revealed that mutated PINK1 leads
to recessive type of PD [159].
Furthermore, there are other factors that contribute to mitochon-
drial dysfunction via several different pathways. Both mutated gluco-
cerebrosidase 1 (GBA 1) gene and quinone oxidase products encourage
the production of ROS. The effect of oxidative damage on the mi-
tochondrial function is due to the selective loss of mitochondrial com-
plex I and alpha-ketoglutarate dehydrogenase complex (KGDHC). This
can downregulate the mitochondrial respiratory system and cause in-
trinsic cell death in PD [159].
Mitochondrial dysfunction also occurs when the voltage-dependent
anions channels (VDACs) are blocked [167]. The study proved that
homocysteine is a kind of putative neurotoxin that inhibits activity of
S.H. Tan et al.
Fig. 5. Illustration of PINK1 and Parkin dysregulation in mitochondria effect on PD.
mitochondrial complex I and leads to loss of dopaminergic neurons as
well as mitochondrial damage [159]. This can reduce the amount of the
important antioxidant, glutathione (GSH) and induce the risk of da-
maged neurons by mitochondria [159,168].
Apart from that, Lon protease, which is found in matrix of mi-
tochondria functions to destroy oxidised and impaired protein. Lon
Protease dysfunction has been shown to associate with the degradation
of mitochondria [169]. The increased ROS level enhances Lon Protease
expression to deal with the damage caused by free radicals. Therefore,
increased expression of Lon Protease along with oxidised protein ac-
cumulation are the indications of neurodegeneration in PD. The study
also revealed that dysfunctional Lon Protease has the ability to inhibit
proteasome activity which eventually results in mitochondrial impair-
ment [170].
7. Role of oxidative stress and ROS in neurodegenerative diseases
ROS are a group of highly reactive oxygen-derived molecules,
characterized by short lifespan due to the unpaired electrons [171,172].
The examples of ROS include free radicals (superoxide, O2−), non-ra-
dicals (hydrogen peroxide, H2O2) and hydroxyl radicals (%OH). They
can be generated exogenously and endogenously in human body.
Meanwhile, their production is normally balanced by antioxidant sys-
tems in the body. [173]. Also, both environmental toxins and chemicals
are believed to be involved in the ROS production as by-products of
their respective metabolisms [174]. In human body, ROS are primarily
produced via mitochondrial respiratory chain [175,176].
Despite being the by-products of cellular metabolism, optimized
level of ROS is essential to initiate pro-survival pathways as well as
cellular signalling from mitochondria to the rest of the cell [172].
Under normal circumstances, ROS induce the redox sensitive signal
cascades via the redox-buffering capacity of intracellular thiols in-
cluding GSH and thioredoxin (TRX) [177]. As for TRX, it mediates the
protein activity through direct binding to them. Due to their partici-
pation in cell signalling, the high ratios of reduced to oxidized forms are
regulated by their respective enzymes (GSH and TRX reductases) [178].
Consequently, the antioxidant enzymes will act against the cellular
oxidative stress through the reduction of H2O2. As the expression of the
enzymes elevates, they enable the cells to survive through oxidant ex-
posures [179]. However, if there is an imbalance between the anti-
oxidant defence and ROS generation, ROS will accumulate in excess
and thus, oxidative stress happens [180]. The oxidative stress is
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Biomedicine & Pharmacotherapy 111 (2019) 765–777
proposed to be associated with the DNA damage, proteins, lipids as well
as activation of apoptosis or autophagy pathways, linking to cell death
[174,181]. It is suggested that the brain is highly susceptible to oxi-
dative stress due to several factors. For instance, ROS formation is
catalysed due to high oxygen demand, high polyunsaturated fatty acids
levels as well as high level of redox-active metals such as iron and
copper located in the brain cell membranes, contributing to neurode-
generative diseases such as AD and PD [180,182].
7.1. Alzheimer’s disease
The gradual neuronal loss in AD is mainly contributed by the ag-
gregation of Aβ plaques and tau tangles [183]. It has been proposed
that oxidative stress is associated with Aβ and tau tangles aggregation
via several major mechanisms such as mitochondrial dysfunction,
protein and DNA oxidation, lipid peroxidation as well as proteins ag-
gregation (Fig. 6).
7.1.1. Oxidative stress/ROS and mitochondrial dysfunction
Excessive accumulation of Aβ will increase ROS accumulation and
result in increased oxidative stress. On the other hand, oxidative stress
promotes both expression and activity of β- and γ-secretases, so the Aβ
production increases [184]. Consequently, they give rise to mitochon-
drial dysfunction [181]. Due to mitochondrial dysfunction, there will
be a reduction of energy metabolism in brain since ATP production is
inhibited [184,185]. This leads to reduced neuronal gene expression
which codes for the subunits of mitochondrial ETC [185]. Meanwhile,
Fig. 6. The connection between ROS, mitochondrial dysfunction, protein, DNA
oxidation, and lipid peroxidation in development of AD.
S.H. Tan et al.
mitochondrial dysfunction impairs the Ca2+ homeostasis [186]. The
accumulation of mitochondrial Ca2+ increases ROS generation and
triggers the opening of permeability transition pore (PTP) [181].
Hence, pro-apoptotic molecules translocate from mitochondria towards
apoptosis, a pathway that promotes neural cell death.
7.1.2. Oxidative stress/ROS and oxidation of protein, DNA and lipid
peroxidation
Furthermore, oxidative stress secondary to excess Aβ provokes AD
through the elevated levels of by-products from protein and DNA oxi-
dation as well as lipid peroxidation. In APP transgenic mice study, had
pronounced elevated H2O2 as well as peroxidation of lipid and protein
levels [184]. Also, ROS-mediated protein oxidation links up the protein
oxidative damage in AD [187]. On top of that, as DNA bases are highly
susceptible to oxidative stress, they will undergo oxidative damage
through some ROS-mediated processes [188]. Therefore, the role of
DNA oxidation in AD is validated when increased oxidative damage on
mitochondrial DNA has been shown in aging and in various regions of
AD brain.
As in lipid peroxidation, their markers such as 4-hydroxynonenal (4-
HNE) and malondialdehyde (MDA) are related to oxidative stress [189].
Lipid peroxidation is a chain reaction where the double bond of un-
saturated fatty acids is attacked by radicals and formation of highly
reactive lipid peroxyl radicals takes places [190]. Due to its ability in
protein modification, 4-HNE inhibits glutamate transporters and trig-
gers dysregulation of intracellular signalling of Ca2+, which eventually
promotes apoptotic cascade [191,192]. Apart protein modification, 4-
HNE is also cytotoxic to neurons as it impedes the function of neuronal
glucose transporter 3. Hence, it is stated that 4-HNE is a marker and
toxin to AD [193]. There are studies to advocate this statement by
proving that increased level of lipid peroxidation markers has been
observed in the temporal lobe of AD [189]. Lipid peroxidation is usually
accompanied by poor capability of antioxidant system in AD; the levels
of antioxidants (e.g. Vitamin C & E, uric acid) and antioxidant enzymes
(e.g. GSH peroxidase, SOD) show profound reduction in patients with
AD [184,185]. The insufficient antioxidant potential in brain will fa-
vour oxidative stress and soon this may result in AD [189].
7.1.3. Oxidative stress/ROS and proteins aggregation
Generally, AD comprises the accumulation of abnormally-folded tau
and Aβ proteins in the brain. The accumulation of aberrant proteins
provokes loss or even death of brain neurons. It has been suggested that
oxidative stress is the key factor for protein aggregation in AD. When
tau proteins encounter oxidative stress, they will undergo hyperpho-
sphorylation and lose their biological function [194]. Similarly, when
Aβ proteins encounter oxidative stress, the structures of β-sheet and
random coil in the proteins increase and thus, misfolding of Aβ proteins
occurs and leads to Aβ aggregation in the brain [195].
Under normal circumstances, proteasome is responsible to eliminate
oxidized and misfolded proteins [196]. Following aggregation, the
aberrant proteins tend to act as the inhibitors of proteasome activity
[197]. When proteasome activity is inhibited, the degradation of oxi-
dized and misfolded proteins will be alleviated [76]. Consequently,
aberrant proteins will accumulate in excess and this will further con-
tribute to ROS production. The abnormal interaction between protein
accumulation and ROS production provokes apoptotic cascade me-
chanism in AD.
7.2. Parkinson’s disease
Unlike AD, PD is manifested by progressive dopaminergic neurons
loss and diminished dopamine levels in the brain [198]. As the brain
needs very high oxygen demand, ROS has become one of the notable
hallmarks to the loss of dopaminergic neurons in PD [199]. It has been
suggested that ROS-mediated DNA damage in PD is linked to several
pathways, such as enhanced metabolism of dopamine, presence of
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Fig. 7. The dopamine metabolism, neuroinflammation can induce ROS/oxida-
tive stress level that give rise to PD.
neuroinflammation and SNCA (Fig. 7).
7.2.1. Oxidative stress/ROS and enhanced dopamine metabolism
Being an unstable molecule, dopamine carries out auto-oxidation
and generates dopamine quinones and free radicals [200]. In healthy
brain, dopamine levels is mediated by monoamine oxidase-A (MAO-A);
however, in brain with PD, MAO-B increases and metabolizes dopamine
predominantly [201]. As a result, H2O2 is formed as the by-product of
MAO-B-mediated dopamine metabolism [202]. Thus, the enhanced
dopamine metabolism could account for the aggregation of toxic radi-
cals like ·OH in the brain [203]. Meanwhile, the dopamine quinones
result from dopamine metabolism will then undergo cyclisation process
and produce highly reactive amino chrome, which provokes the O2−
production [204]. As more ROS are being generated, the oxidative
stress occurs which results in dopaminergic neural cell death and causes
PD.
7.2.2. Oxidative stress/ROS and neuroinflammation
It is proposed that the relationship between oxidative stress and
neuroinflammation contributes to the neurodegeneration in PD [205].
Under normal circumstance, microglia serve as phagocytes to protect
the CNS against microbial pathogens as well as the mediators of
adaptive and innate immune system [206]. In PD, they become acti-
vated and cause neuronal injury via the production of ROS and pro-
inflammatory factors [207]. Activated microglia are crucial sources of
ROS (e.g. O2−) so they become the culprits for the occurrence of oxi-
dative stress in brain with PD. Furthermore, ROS is able to activate the
pro-inflammatory pathways, which in turn actuate detrimental en-
vironment for susceptible dopaminergic neurons [207].
This has been proven when the existence of activated microglia
along with increased level of cytokines is found in the SNPC of patients
with PD [207,208]. Therefore, neuronal death secondary to activated
microglia will further promote the activation of microglial cells, de-
veloping a neurotoxic vicious cycle of inflammation perpetuating tissue
injury [209]. All these processes will then lead to neurodegeneration in
PD.
7.2.3. Oxidative stress/ROS and SNCA
Apart from dopamine, the discovery of SNCA proteins has provided
a vital insight into the pathophysiology of oxidative stress-mediated PD.
Being a natively unfolded neuronal protein, SNCA is responsible to
reuptake synaptic vesicle, store and compartmentalize neuro-
transmitters (e.g. dopamine) [210]. In patients with PD, SNCA genes
are mutated and multiplicated, so they are more prone to form ag-
gregates [211]. Besides that, oxidative stress is able to modify the nu-
clear membrane and translocate SNCA to the nucleus, where formation
of SNCA-histone complexes takes place, so this will lead to SNCA oli-
gomerization into insoluble fibrils [212]. These insoluble fibrils will
then induce the deposition of abnormal protein aggregates, known as
Lewy bodies [213].
S.H. Tan et al.
Fig. 8. Conceptual model of candidate pathways contributing to AD, PD neu-
rodegeneration.
Besides the impact of oxidative stress due to the presence of SNCA
fibrils, the mutated SNCA is also related to elevated production of ROS
[214]. Additionally, this notion has been validated when over-
expression of mutant SNCA enhances the risk of dopamine toxicity
[215], leading to defects in mitochondria and apoptosis, which further
increases their vulnerability towards oxidative stress [216]. These re-
sults explain that ROS enhances SNCA accumulation, which in turn
increases ROS, creating a dual pathogenic mechanism leading to neu-
rodegeneration.
In short, through a detailed review, the major pathways common to
AD and PD have been discerned (Fig. 8). These pathways are helpful to
discover new targets for further study as well as biomarker and drug
development.
8. Conclusions and future directions
In conclusion, neurodegenerative diseases such as AD and PD are
usually untreatable as the clinical manifestations showed the perma-
nent loss of specific neurons in patients. There are several risk factors
contributed to AD and PD, including aging, genetic and environmental
factors. Taken together, the selected pathways perturbations are di-
rectly or indirectly generated by several factors involved in PD, AD
neurodegenerative diseases. However, our understanding of the me-
chanisms involved remains rudimentary at best. Through a detailed
review of pathways and molecular events, numerous pathways common
to AD and PD have been identified, which nominate promising new
targets for further study as well as biomarker and drug development.
On top of that, increasing evidence suggests that UPS dysregulation,
aberrant alternative splicing, mitochondrial dysfunction and over-
expression of ROS are largely operative in the neurodegenerative dis-
eases especially AD and PD. These findings build on established notions
of complex disease aetiology, with multiple processes presumed to in-
fluence neurodegeneration and clinical outcomes in AD, PD, and related
disorders. They also advance the understanding of mechanisms likely to
be crucial in maintaining brain structure and function during normal
aging.
Despite the explanations of the biological pathways in this review,
more studies and researches are still required to support the causal
relationship between the biological pathways and the neurodegenera-
tive diseases as some of the mechanisms remain obscure. These insights
also suggest that biomarker and treatment strategies may require si-
multaneous targeting of multiple components, including some specific
to disease stage, in order to assess and modulate neurodegeneration.
More broadly, pathways and networks can serve as vehicles for in-
tegrating findings from diverse studies of neurodegeneration. There are
many active strategies for large scale omics analysis of neurodegen-
erative disease, and findings that converge across these multiple study
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Biomedicine & Pharmacotherapy 111 (2019) 765–777
designs can provide confirmatory evidence that is crucial for efficient
clinical translation.
Pathways will provide ideal vehicles for integrating relevant find-
ings from experimental study. Although treatments are available for
both diseases, the role of treatment is primarily to prevent or delay the
progress of the diseases instead of fully overcoming the diseases. The
challenge in the near future will be to determine effective drugs to
tackle the dysregulated biological pathways for the treatment of neu-
rodegenerative diseases. Drug discovery for AD and PD treatments are
still ongoing and establishing the most desirable design features with
appropriate chemical properties is an interested area of research. A
challenge for future studies is to unravel the molecular nature of these
major pathways interactions for drug research. There is compelling
reason to hope that efforts to high throughput omics based studies will
ultimately lead to new biomarker and therapeutic approaches in AD,
PD. Therefore, broader and deeper knowledge on drug aspects are re-
quired for the target-specific treatments so that lifespans among the
general population can be prolonged in future.
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