Annual Review of Neuroscience
Parkinson’s Disease Genetics
Annu. Rev. Neurosci. 2021. 44:87–108
The Annual Review of Neuroscience is online at
neuro.annualreviews.org
https://doi.org/10.1146/annurev-neuro-100720-
034518
Copyright © 2021 by Annual Reviews.
All rights reserved
and Pathophysiology
Gabriel E. Vázquez-Vélez1,2 and Huda Y. Zoghbi1,2,3,4
1
Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston,
Texas 77030, USA
2
Program in Developmental Biology and Medical Scientist Training Program, Baylor College of
Medicine, Houston, Texas 77030, USA
3
Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine,
Houston, Texas 77030, USA; email: hzoghbi@bcm.edu
4
Howard Hughes Medical Institute, Houston, Texas 77030, USA
Keywords
Parkinson’s disease, genetics, α-synuclein, LRRK2, GBA, vesicular
trafficking, lysosome, mitochondria
Abstract
Parkinson’s disease (PD) is a common neurodegenerative disorder charac-
terized by degeneration of the substantia nigra pars compacta and by ac-
cumulation of α-synuclein in Lewy bodies. PD is caused by a combination
of environmental factors and genetic variants. These variants range from
highly penetrant Mendelian alleles to alleles that only modestly increase dis-
ease risk. Here, we review what is known about the genetics of PD. We also
describe how PD genetics have solidified the role of endosomal, lysosomal,
and mitochondrial dysfunction in PD pathophysiology. Finally, we highlight
how all three pathways are affected by α-synuclein and how this knowledge
may be harnessed for the development of disease-modifying therapeutics.
87
 Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
GENETICS OF PARKINSON’S DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
SNCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
LRRK2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
VPS35 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
GBA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Genome-Wide Association Studies Identify Common Variants That Increase
Parkinson’s Disease Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Targeted Genetic Studies Identify Additional Rare Parkinson’s
Disease–Associated Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Autosomal Recessive Juvenile-Onset Parkinsonism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
α-SYNUCLEIN AND PARKINSON’S DISEASE PATHOPHYSIOLOGY . . . . . . . . 95
α-Synuclein Is the Most Abundant Protein in Lewy Bodies . . . . . . . . . . . . . . . . . . . . . . . 95
Pathways Involved in Parkinson’s Disease Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Vesicular Trafficking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
The Lysosome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
The Mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Other Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Harnessing Parkinson’s Disease Pathophysiology to Develop
Disease-Modifying Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

INTRODUCTION
Parkinson’s disease (PD) is the second most common neurodegenerative disease, with its preva-
lence doubling from 1990 to 2016 (Dorsey et al. 2018). PD is defined by four cardinal motor
symptoms: (a) tremor at rest, (b) bradykinesia, (c) rigidity, and (d) postural instability. PD is also
characterized by a variety of nonmotor symptoms, which include constipation, depression, de-
mentia, anosmia, and sleep disorders ( Jankovic 2008). PD is clinically heterogeneous in terms of
onset and predominant symptoms. Most patients have disease onset in their 60s (late onset), but
there are patients in which onset occurs earlier (young onset). Additionally, some patients present
with tremor as the most prominent symptom, while others present with postural instability and
gait difficulty (Thenganatt & Jankovic 2014).
The first hallmark of PD is the degeneration of neurons in the substantia nigra pars com-
pacta (SNc). Importantly, patients present with motor symptoms when approximately 50–80%
of all nigral dopaminergic neurons have degenerated (Cheng et al. 2010). This degeneration de-
creases dopamine release in the striatum, which alters the circuits by which the basal ganglia con-
trol movement (DeMaagd 2015). For this reason, dopamine replacement/agonism and deep brain
stimulation of basal ganglia nuclei are currently used to manage PD motor symptoms (Limousin
& Foltynie 2019, Okun 2017). Notably, these therapies do not affect disease progression, nor do
they directly address nonmotor symptoms.
The second hallmark of PD is the presence of proteinaceous aggregates in neurons called
Lewy bodies (LBs) and Lewy neurites. These aggregates have been observed both inside and
outside the SNc. In fact, Braak et al. (2003) devised a six-stage system to classify PD patient brains
based on the extent of Lewy pathology. PD can be classified as a synucleinopathy because the

88 Vázquez-Vélez • Zoghbi
proteinaceous component of LBs is composed chiefly of α-synuclein (α-syn) (Spillantini et al.
1998). Importantly, dementia with Lewy bodies (DLB) is another synucleinopathy that shares an
overlap of symptoms with PD. It is characterized by dementia with visual hallucinations early in
the disease and subsequent development of parkinsonian motor symptoms (Arnaoutoglou et al.
2019).
There are multiple environmental factors that influence PD risk, which include mitochondrial
poisons such as MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) (Langston 2017), expo-
sure to pesticides (Pezzoli & Cereda 2013), traumatic brain injury (Gardner et al. 2015), and aging
(Reeve et al. 2014). Apart from environmental factors, genetic variants can also influence PD risk.
These variants range from common alleles with low penetrance to rarer highly penetrant alleles
that dramatically increase risk or cause autosomal dominant forms of the disease (Shulman et al.
2011). Here, we synthesize what is known about PD genetics in an effort to create a model of
disease pathogenesis.

GENETICS OF PARKINSON’S DISEASE

PD genetics offers a valuable window into the mechanism of the disease by highlighting specific
molecular pathways and their effects at the cellular level. This section summarizes the complex
genetics of PD with a focus on the best-characterized genes. Table 1 lists the loci associated with
monogenic forms of parkinsonism, but loci without known causal genes are excluded. Notably,
causes of atypical parkinsonism (AP) are included. AP can be defined as syndromes characterized
by the presence of the four previously mentioned cardinal motor signs of PD, in addition to early

Table 1 Selected genetic loci associated with familial Parkinsonism

Inheritance
Locus Locus map pattern Gene Clinical features Reference
PARK1/4 4q22.1 AD SNCA Early onset, rigidity, cognitive Polymeropoulos et al.
impairment 1997
PARK2 6q26 AR PRKN Juvenile onset, dystonia Kitada et al. 1998
PARK6 1p36.12 AR PINK1 Early onset, dystonia Valente et al. 2002
PARK7 1p36.23 AR PARK7 Early onset, dystonia Abou-Sleiman et al.
2003
PARK8 12q12 AD LRRK2 Classic PD Funayama et al. 2002
PARK9 1p36.13 AR ATP13A2 Early onset, cognitive impairment Di Fonzo et al. 2007
PARK14 22q13.1 AR PLA2G6 Early onset, cognitive impairment, Paisán-Ruíz et al. 2009
dystonia
PARK15 22q12.3 AR FBXO7 Early onset Di Fonzo et al. 2009
PARK17 16q11.2 Unknown VPS35 Adult onset, cognitive impairment, Zimprich et al. 2011
dystonia
PARK19a/b 1p31.3 AR DNAJC6 Early onset, cognitive impairment Edvardson et al. 2012
PARK20 21q22.11 AR SYNJ1 Early onset, seizures Krebs et al. 2013
PARK21 3q22 AD DNAJC13 Classic PD Vilariño-Güell et al.
2014
PARK23 15q22.2 AR VPS13C Early onset, rapid progression, Lesage et al. 2016
cognitive impairment

The inheritance pattern, gene, clinical features, and relevant reference for each locus are provided. Classic PD refers to symptoms that resemble sporadic
PD. Abbreviations: AD, autosomal dominant; AR, autosomal recessive; PD, Parkinson’s disease.

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 and severe presentations of symptoms like dementia, frequent falls, ocular dysmotility, prominent
dysautonomia, and/or ataxia (McFarland 2016). The rest of this review focuses on the genetics of
PD.

SNCA
SNCA (PARK1/4) is a five-exon gene located on chromosome 4 (4q22.1) and is one of three par-
alogs that form the synuclein family. The synucleins are presynaptic proteins exclusively expressed
in vertebrates that also include SNCB (β-syn) and SNCG (γ-syn) (George 2002). SNCA codes for
α-syn, a 14-kDa protein that is widely expressed throughout the brain (Iwai et al. 1995). α-Syn
has been reported to aid in SNARE complex formation, promote long-term maintenance of the
presynaptic compartment, and regulate the release of dopaminergic vesicles. β-Syn has 78% ho-
mology to α-syn and is coexpressed with α-syn throughout the brain and in the presynaptic com-
partment. Meanwhile, γ-syn has 67% homology and is expressed in the peripheral nervous system,
specific central neuronal subtypes, and in breast, colon, and pancreatic cancers (Bendor et al. 2013,
Burré et al. 2018). Although only α-syn is thought to be involved in PD pathophysiology, decreased
levels of SNCB transcript have been found in certain patients with DLB, and in vitro studies sug-
gest that β-syn may antagonize α-syn-induced aggregation and toxicity (Beyer et al. 2012).
Point mutations in SNCA (NM_000345.4) were the first identified cause of autosomal dom-
inant PD (Polymeropoulos et al. 1997) and led to the discovery that α-syn is the major protein
component of LBs (Spillantini et al. 1998). In addition to p.A53T, other reported pathogenic
SNCA variants are p.A30P, p.E46K, and p.G51D (Krüger et al. 1998, Lesage et al. 2013, Zarranz
et al. 2003). All of these missense changes occur within the membrane binding domain of α-syn
(Table 2).
The clinical presentation of people with SNCA mutations depends on the variant. In addition,
there is intrafamilial heterogeneity. In general, all patients have early onset of disease (as early
as 19 years old), with most cases developing symptoms when patients are 40–60 years old. All
patients present with the classical PD motor symptoms. However, patients with p.A53T, p.E46K,
or p.G51D mutations also have early cognitive impairment. Pathologically, these patients show
degeneration of the SNc and widespread accumulation of LBs as well as additional features such
as cortical thinning (p.A53T) and involvement of the motor cortex (p.G51D).
Soon after the discovery of these point mutations, a disease-causing triplication of the
wild-type SNCA locus was described in a family with autosomal dominant parkinsonian motor
signs, early onset of symptoms (mean age 36 years), and prominent cognitive defects (Singleton
et al. 2003). The four patients from this family who have been studied neuropathologically
had complete loss of the SNc as well as severe cortical and hippocampal atrophy. Microscopic
examination revealed widely distributed LBs throughout the brain and severe loss of cortical and
hippocampal neurons with gliosis (Muenter et al. 1998, Spellman 1962). Subsequently, over 19
families with autosomal dominant disease caused by duplications in wild-type SNCA have been
reported (Konno et al. 2016).
The discovery of these kindreds provides several key insights into PD pathophysiology. First,
it suggests that increases in wild-type α-syn levels are sufficient to drive PD pathogenesis. Second,
there is a correlation between gene dosage and symptoms, where SNCA triplication patients de-
velop symptoms earlier than duplication patients (Trinh et al. 2014). Third, this suggests that less
penetrant variants of SNCA that cause small changes in α-syn levels might increase the risk for PD.
This latter prediction is validated by a recent study that found that a variant in the SNCA enhancer
associated with increased PD risk also decreases the binding of the transcriptional repressors and
promotes SNCA expression (Soldner et al. 2016).

90 Vázquez-Vélez • Zoghbi
Table 2 Pathogenic SNCA variants
Variant and
amino acid
sequence Age of onset Clinical features Pathological features Reference(s)
c.G>209A, Youngest: 23 years Parkinsonian motor Degeneration of the Athanassiadou et al. 1999,
p.A53T Average: 47 years symptoms responsive to SNc with widespread Bostantjopoulou et al.
levodopa with early LBs 2001, Ki et al. 2007,
cognitive impairment, as Cortical thinning with Markopoulou et al. 2008,
well as myoclonus and vacuoles Polymeropoulos et al.
autonomic dysfunction Some patients have 1997, Puschmann et al.
neurofibrillary tangles 2009, Spira et al. 2001,
and TDP-43 Xiong et al. 2016
inclusions
c.G>88C, Average: 60 years Tremor-dominant PD, Degeneration of the Krüger et al. 1998, Seidel
p.A30P responsive to levodopa SNc with widespread et al. 2010
LBs
c.G>188A, Range: 50–65 years Parkinsonian motor Mild degeneration of Zarranz et al. 2003
p.E46K symptoms responsive to the SNc with
levodopa with early widespread LBs
cognitive impairment
c.C>152A, Range: 19–61 years Parkinsonian motor Massive nigral and locus Kiely et al. 2015, Lesage
p.G51D symptoms as well as coeruleus et al. 2013
pyramidal (motor neuron) degeneration with
signs, which include widespread LBs or
spasticity and exaggerated GCIs
tendon reflexes

For each variant, the nucleotide and amino acid change is provided along with known kindreds, clinical and pathological features, and relevant references.
All mutations are known to be inherited in an autosomal dominant pattern. Abbreviations: GCI, glial cytoplasmic inclusion; LB, Lewy body; PD, Parkinson’s
disease; SNc, substantia nigra pars compacta.

LRRK2
Variants in LRRK2 (PARK8) also cause autosomal dominant PD (Funayama et al. 2002, Paisán-
Ruíz et al. 2004, Zimprich et al. 2004b). The age of onset varies between different LRRK2
pathogenic variants and kindreds (Trinh et al. 2014). LRRK2 codes for leucine-rich repeat kinase
2 (LRRK2), a 253-kDa protein with multiple functional domains that is expressed in the brain,
lungs, kidneys, and the immune system (Giasson et al. 2006, Higashi et al. 2007). LRRK2 has both
GTPase and kinase activity, which are carried out by a Ras of complex proteins (ROC)/C-terminal
of Ras (COR) and a kinase domain, respectively (Araki et al. 2018, Ito et al. 2007). The rest of the
domains of this protein are involved in protein-protein interactions.
Apart from these highly penetrant alleles, there are other more common LRRK2 variants that
modify PD risk (Cookson 2015, Nalls et al. 2019) (Table 3). Mutations in LRRK2 are the sec-
ond most common genetic risk factor for sporadic PD, accounting for up to 1% of total disease.
LRRK2 variants explain 70% of PD in North Africans and 29% of familial PD in Ashkenazi Jewish
individuals (Healy et al. 2008, Thaler et al. 2009).
All of the highly penetrant variants in LRRK2 are thought to increase kinase activity directly
or indirectly (Cookson 2015). Moreover, a recent report showed that LRRK2 kinase activity is
increased in sporadic PD patient brains (Di Maio et al. 2018). This, and the fact that Lrrk2−/−

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Table 3 LRRK2 variants associated with Parkinson’s disease
Mutation and amino Protein domain affected and
acid sequence Mutation consequence proposed effect on function Reference(s)
c.4309A>C AD PD ROC, decreases GTPase Cookson 2015
p.N1437H activity
c.4321C>T/G/A
p.R1441C/G/H/S
c.5096A>G COR, decreases GTPase
p.Y1699C activity
c.6055G>A Kinase domain, increases kinase
p.G2019S activity
c.6059T>C
p.I2020T
c.1464A>T Increased sporadic PD Sequence in between ARM and Christensen et al. 2018, Li et al.
p.A419V risk ANK domains, effect 2015, Heckman et al. 2013, Ross
unknown et al. 2011, Tan et al. 2010, Zhang
c.7153G>A WD40, increases kinase activity et al. 2017
p. G2385R
c.4883G>C COR, increases kinase activity
p.R1628P
c.4937T>C
p.M1646T
c.3494T>C- c.4193G Decreased sporadic PD Sequence in between ARM and
>A-c.4269G>A risk ANK domains–ROC–ROC,
p.N551K-R1398H- reduces kinase activity
K1423K

For each mutation, the nucleotide and amino acid change is provided along with inheritance patterns, the effect on the LRRK2 protein function, and
relevant references. Abbreviations: AD, autosomal dominant; COR, C-terminal of Ras; PD, Parkinson’s disease; ROC, Ras of complex proteins.

mice lack any PD-like phenotypes (Herzig et al. 2011), has led to the hypothesis that increased ki-
nase activity is what drives the pathogenic effect of LRRK2. Concordantly, heterozygous carriers
of null variants of LRRK2 have reduced LRRK2 protein levels but no associated clinical phe-
notype (Whiffin et al. 2020), while patients with the PD-causing p.G2019S variant have higher
cerebrospinal fluid LRRK2 levels than controls (Mabrouk et al. 2020). Moreover, LRRK2 kinase
inhibition rescues the endolysosomal defects induced by rotenone (a pesticide that increases PD
risk) (Rocha et al. 2020). Notably, the gain-of-function mechanism has been challenged by a re-
port that shows that Lrrk1−/− ; Lrrk2−/− mice have dopaminergic neuron degeneration as well
as PD-like motor phenotypes. The authors hypothesized that this discrepancy is due to partial
compensation of Lrrk2 function by Lrrk1 (Giaime et al. 2017).
The clinical phenotype of LRRK2-PD patients resembles that of sporadic PD (Zimprich et al.
2004a). The neuropathology of LRRK2 patients is variable (Hasegawa et al. 2009, Martí-Massó
et al. 2009, Rajput et al. 2006, Vilas et al. 2019), with most, but not all, findings being similar
to sporadic PD. Some patients lack LBs, instead showing tau or TDP-43 inclusions. Given the
complexity of the effects of LRRK2 mutations on its biology, it is perhaps not surprising that
different mutations result in different pathological phenotypes, or that they result in incomplete
penetrance. It is also unclear if the tau and TDP-43 inclusions are causing the patient’s symptoms
or if they are an incidental finding.

92 Vázquez-Vélez • Zoghbi
VPS35
VPS35 (PARK17) codes for vacuolar protein sorting 35, one of the core proteins in the retromer, a
heteropentameric protein complex responsible for retrograde sorting of proteins from the endo-
some to the cell membrane and trans-Golgi network, and vice versa. The c.1858G>A (p.D620N)
variant, found predominantly in Caucasian populations, causes autosomal dominant PD with high
but incomplete penetrance (Vilariño-Güell et al. 2011, Wider et al. 2008, Williams et al. 2017,
Zimprich et al. 2011). This variant accounts for an estimated 0.1–1% of patients with familial
PD. Patients with VPS35 p.D620N have a similar clinical presentation to those with idiopathic
PD, with an average age of onset ranging from 48.3 to 53 years old depending on the kindred
(Vilariño-Güell et al. 2011, Zimprich et al. 2011). Whether this variant exerts its effect through
toxic gain-of-function, haploinsufficiency, or a dominant negative effect remains to be determined.
Other rare VPS35 variants have been reported, but whether they cause PD is unknown (Williams
et al. 2017). To date, it is not clear whether there is α-syn pathology in patients with VPS35 variants.
This is because the only data available are based on a single autopsy that had limited pathological
studies (Wider et al. 2008).

GBA
GBA codes for β-glucocerebrosidase (GCase), a lysosomal enzyme that breaks down glucosylce-
ramide (GluCer) into glucose and ceramide (Brady 1965). Homozygous GBA mutations cause
a recessive lysosomal storage disorder called Gaucher’s disease (GD). This disease mainly affects
the liver, spleen, and bones, although it can have central nervous system involvement. GD patients
are classified on the basis of brain involvement, with GD type 1 patients lacking the neurological
symptoms that are associated with types 2 and 3. However, heterozygous GBA mutation carriers
have a five- to eightfold increased risk of PD depending on the variant and the population studied
(Sidransky et al. 2009).
There are over 100 variants in the GBA gene that can cause GD by reducing the enzymatic
activity of GCase, destabilizing it, or altering its lysosomal localization (Stirnemann et al. 2017).
GBA variants that cause GD in homozygosity increase the risk of PD or DLB in heterozygosity
(Aharon-Peretz et al. 2005, Sato et al. 2005, Sidransky et al. 2009), and GBA variants represent the
most common genetic risk factor for PD. Interestingly, two GBA variants (E365K and T408M)
increase PD risk but do not cause GD (Duran et al. 2013, Mallett et al. 2016). In a large multi-
center study, researchers found that the odds ratio of all PD patients for carrying at least one GBA
mutation was 5 (Sidransky et al. 2009).
Clinically, PD patients with mild GBA mutations present with motor symptoms similar to idio-
pathic PD and respond to levodopa early on. However, the clinical phenotype is connected to the
variant in question, with some patients having early onset of disease, including dementia, higher
frequency of sleep disorders, and higher frequency of psychiatric symptoms such as depression
and anxiety (Brockmann et al. 2011, Liu et al. 2016, McNeill et al. 2012). Neuropathologically,
the brains of these patients show features consistent with PD, including nigral degeneration and
widespread LBs (Braak stages 5–6) (Neumann et al. 2009).

Genome-Wide Association Studies Identify Common Variants That Increase

Parkinson’s Disease Risk
Genome-wide association studies (GWASs) have been used to identify numerous loci associated
with PD risk (Chang et al. 2017, Nalls et al. 2019). GWASs operate under the common disease–
common variant hypothesis. The idea is that there are common variants with low penetrance that

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Table 4 Genes associated with single nucleotide polymorphisms that modulate Parkinson’s disease risk
Category Candidate genes
Cytoskeleton CAB39L, TUBG2, MAPT, DNAH17, ANK2, PDLIM2, SORBS3
Endosomal and vesicular VAMP4, SIPA1L2, SNCA, CHMP2B, LRRK2, BIN3, RIMS1, DDRGK1, SYT4, ATP6V0A1,
trafficking GBF1, ARHGAP27, SH3GL2
Immune system FCGR2A, IL1R2, HLA-DRB6, HLA-DQA1, FYN, CD19, CD38, NOD2, TRIM40, FAM49B,
ITIH3, ITIH4, TLR9, STAB1
Ion channels, transporters, and KCNS3, KCNIP3, TMEM163, SCN3A, CHRNB1, CLCN3, GCH1, NCKIPSD, CAMK2D
neurotransmitter signaling
Lipid metabolism and signaling SPTSSB, ELOVL7, DGKQ
Lysosome and autophagosome GBA, CTSB, GALC, KAT8, TMEM175
Mitochondria SLC41A1, COQ7, VPS13C, BAG3, MCCC1, CRLS1, MICU3
Nucleus and gene regulation NUCKS1, CCNT2, SATB1, KPNA1, MED12L, LCORL, MBNL2, MEX3C, MIR4697, TOX3,
UBTF, LSM7, BRIP1, ASXL3, RPS6KL1, PSMC3IP, SREBF1, RAI1, KANSL1, RNF141,
RPS12, CDC71, PHF7, NUPL2, ZNF184
Ubiquitin pathway UBAP2, BAP1, KLHL7
Miscellaneous ITPKB, LINC00693, DYRK1A, OGFOD2, FAM171A2, ZNF646, FAM47E, FBRSL1,
MIPOL1, SCAF11, PAM, TMEM229B, CRHR1, STH, SPPL2C, DLG2, C5orf24, C8orf58,
GS1–124K5·11, ALAS1, NISCH, GPNMB, FAM200B, STK39

All genes are organized into functional categories. The miscellaneous category is reserved for genes with unknown function or with functions that do not
fit into the other categories.

individually increase risk minimally but collectively cause a significant amount of risk (Billingsley
et al. 2018). Essentially, researchers track the association of single nucleotide polymorphisms
(SNPs) to disease risk by performing large sample comparisons of PD patients and healthy
controls. If the frequency of a SNP is significantly different between groups, then it is said to be
associated with disease. This approach has been fruitful, with over 90 risk loci identified (Table 4)
(Nalls et al. 2019) and the development of a polygenic risk score (PRS) that accounts for 16–36%
of the genetic contribution to idiopathic nonmonogenic disease. A high PRS correlates with an
increased odds ratio (on average 3.74–6.24, depending on the method used) of developing PD.
Because multiple genes are often linked to the SNP identified in the GWAS (linkage dis-
equilibrium), it is challenging to identify the gene driving the PD risk. To address this challenge,
studies have used bioinformatic approaches to assess the effect of variants on protein sequence
and expression levels (expression quantitative loci). Despite these limitations, the fact that several
genes (SNCA, GBA, LRRK2, and VPS13C) have both highly penetrant variants that cause famil-
ial PD and more common lowly penetrant alleles that increase PD risk lends credibility to the
approach (Nalls et al. 2019).

Targeted Genetic Studies Identify Additional Rare Parkinson’s

Disease–Associated Variants
Other more targeted human genetic approaches have also identified rare alleles that are significant
risk factors for disease. First, other lysosomal storage disorder genes besides GBA have been im-
plicated in PD risk, including SMPD1, CTSD, SLC17A5, and ASAH1 (Alcalay et al. 2019, Robak
et al. 2017). Second, GBA1 and SMPD1 have been found (in addition to MCOLN1, another lyso-
somal gene) to be associated with the presence of LBs in postmortem brains (Clark et al. 2015).
Third, variants in SCARB2, the gene that codes for the GCase trafficking protein lysosomal inte-
gral membrane protein-2 (LIMP-2), also increase PD risk (Hopfner et al. 2013).

94 Vázquez-Vélez • Zoghbi
Autosomal Recessive Juvenile-Onset Parkinsonism
Autosomal recessive juvenile-onset parkinsonism (ARJP) is characterized by the onset of parkin-
sonian motor symptoms during the teen years (although some have later onset) and responsive-
ness to levodopa (Yamamura 2010, Yamamura et al. 1973). This disease is caused by mutations
in PARKN (Kitada et al. 1998) and PINK1 (Valente et al. 2004). Typically, ARJP patients have
nigral degeneration but lack LB pathology. There have been some case reports of older patients
with PARKN variants that have LBs at autopsy, but these are likely to be incidental findings that
are occurring concurrently with, but not because of, ARJP pathology (Doherty & Hardy 2013,
Farrer et al. 2001, Hayashi et al. 2000). Importantly, ARJP patients have motor symptoms caused
by nigral degeneration with little disease progression over the 30–40 years they live with the dis-
ease (Cookson 2008). Moreover, recent studies have not found any association between PARKN or
PINK1 variants and PD (Krohn et al. 2020a, Yu et al. 2020). Because patients with these variants
do not recapitulate the natural history of PD, and most lack LB pathology, many consider ARJP
a separate entity that mimics some features of PD.
PARKN codes for E3 ubiquitin-protein ligase parkin (Parkin), and PINK1 codes for a kinase of
the same name. In both genes, many mutations have been identified that compromise the ability
of these proteins to regulate mitochondrial health (Haelterman et al. 2014). This mechanism was
elucidated using fruit fly genetics. Parkin-deficient flies had defects in sperm development, muscle,
and some dopaminergic neurons. These defects were explained by abnormal mitochondrial mor-
phology. This phenotype was also found in pink1 mutant flies. Moreover, parkin overexpression
in fruit flies rescued pink1 knockout-induced defects, but not vice versa, suggesting that these two
genes are in the same pathway, and parkin acts downstream of pink1 (Clark et al. 2006, Park et al.
2006, Pickrell & Youle 2015).

α-SYNUCLEIN AND PARKINSON’S DISEASE PATHOPHYSIOLOGY

α-Synuclein Is the Most Abundant Protein in Lewy Bodies
α-Syn has long been known to be the major proteinaceous component of LBs (Spillantini et al.
1998). Ultrastructural analysis of LBs showed that they are composed of fibrillar exteriors and
granular cores that contain proteins as well as lipids and organelles with various reported mor-
phologies (Shults 2006). More recent studies suggest that LBs resemble caged wheel–like struc-
tures where negatively charged species of α-syn (pS129-α-syn) form the outer layer of the aggre-
gate, and hydrophobic species of α-syn (C-terminal truncated) lie closer to a center composed
chiefly of lipids (Moors et al. 2019). These recent studies also highlighted that the lipid core is
composed of mitochondrial and autophagosomal membranes (Shahmoradian et al. 2019). This
suggests that α-syn toxicity may be mediated through the dysregulation of these organelles, a hy-
pothesis that has been supported by recent studies in neuron culture models (Mahul-Mellier et al.
2020).
As discussed previously, postmortem studies have revealed that PD pathology occurs in a
caudo-rostral anatomic progression (Braak et al. 2003). Additionally, key studies found that het-
erologous fetal grafts implanted in the striata of PD patients contained α-syn aggregates upon
autopsy (Li et al. 2008). This led to a model that suggests that α-syn pathology may spread from
the brain stem to the rest of the brain in a stepwise manner.
The enteric nervous system has been hypothesized to be one of the sources of α-syn spreading
because constipation is a prodromal symptom of PD ( Jankovic 2008), there is an epidemiological
link between inflammatory bowel diseases and PD (Villumsen et al. 2019), and pathogenic α-syn
aggregates have been found in the enteric nervous system (Barrenschee et al. 2017) and in the

www.annualreviews.org • Parkinson’s Genetics and Pathophysiology 95

 dorsal motor nucleus of the vagus nerve (Braak et al. 2003) of patients. After spreading to the
vagus nerve, α-syn pathology could then spread to the dorsal motor nucleus of the vagus in the
brain stem and to the rest of the brain in accordance with the Braak stages. It is also possible that
the olfactory bulb acts as a source, because anosmia is a common PD symptom ( Jankovic 2008),
and α-syn pathology of Braak stage 1 patients also can affect the anterior olfactory nucleus (Braak
et al. 2003).
Because of these clinical observations, several groups have generated animal and cellular mod-
els that mimic α-syn spreading. One strategy has been to aggregate α-syn in vitro as preformed
fibrils (PFFs) and inject them into the brain at low concentrations. These PFFs can act as seeds
for the aggregation of endogenous α-syn and spreading of pathology (Luk et al. 2012). When in-
jected into the enteric nervous system of mice, PFFs can induce α-syn spreading into the brain,
which leads to nigral degeneration and motor symptoms (Kim et al. 2019). This effect is specific
to the α-syn PFFs because the authors showed that the spread does not occur in animals with
vagotomy or who are Snca−/− . These data suggest that it is possible for α-syn to spread from the
gut, as hypothesized by Braak et al. (2003), but it is not clear how often this happens in PD or at
what stage of the disease. Researchers have also isolated α-syn-positive aggregates from different
synucleinopathies and have found that there are different strains of aggregated α-syn that behave
and spread differently when injected into the mouse brain (Peng et al. 2018).

Pathways Involved in Parkinson’s Disease Pathogenesis

Despite many remaining unanswered questions, we now know of three major interconnected cel-
lular pathways that are altered and involved in PD pathogenesis: (a) vesicular trafficking, (b) lyso-
somal function, and (c) mitochondrial maintenance (Figure 1). It is also clear that all of these
pathways are tied to α-syn biology.

Vesicular Trafficking
α-Syn has been shown to compromise the function of every step of the vesicular pathway. First,
α-syn inhibits the docking of endoplasmic reticulum (ER) vesicles to the Golgi, which results in
ER stress. This was demonstrated by the fact that overexpression of Rab proteins that promote
forward movement through the trans-Golgi network was sufficient to rescue the toxicity of α-syn
in multiple model systems (Cooper et al. 2006, Gitler et al. 2008). Subsequent studies validated
these findings in dopaminergic neurons derived from various PD patients (Chung et al. 2013,
Heman-Ackah et al. 2017, Tardiff et al. 2013). Second, in patient dopaminergic neurons, α-syn also
compromises the targeting of Golgi vesicles toward the lysosome. This phenotype was rescued by
pharmacological stimulation of NEDD4, an E3 ligase that promotes this vesicular movement and
directly promotes α-syn lysosomal degradation (Chung et al. 2013, Tardiff et al. 2013, Tofaris et al.
2011).
LRRK2 is also associated with vesicular trafficking. The best-characterized targets for LRRK2
kinase activity are Rab GTPases (Steger et al. 2016). Rabs cycle between different subcellular
compartments by using their GTPase activity to switch from binding GTP or GDP. LRRK2
phosphorylation locks the Rabs in a GDP-bound active state where they localize to endolysoso-
mal compartments and promote the release of lysosomal contents to prevent lysosomal overload.
Importantly, Rab29 (Rab7L1) has been shown to recruit LRRK2 to this compartment, as well as
to the trans-Golgi network, and facilitate the phosphorylation of other Rabs (Eguchi et al. 2018,
Purlyte et al. 2019). Moreover, Rab29 is located within the PARK16 locus, which suggests that
LRRK2 and Rab29 cause PD through the same pathway (Simón-Sánchez et al. 2009, Tucci et al.

96 Vázquez-Vélez • Zoghbi
 Variants
V
Var i and
CNVs in SNCA

uclear
Nuclear ?
function

Variants in
VPS35

En
PLA2GC

do
so
me
Endoplasmic
doplas
asmm reticulum Retromer
Golgi
olgi
gi protein
pr
pr sorting
Variants in
ALAS1 Sphingolipid
COQ7 and ceramide
DJ-1 accumulation
α-Synuclein Variants in
Va
FBXO7 accumulation Variants in LLRRK2
Rotenone, LRRK2 ATP13A2 GAK
paraquat MCCC1 ASAH1 RAB7L1
R A
PARKIN Oxidative CTSB
PINK1 stress GALC
VPS13C GBA1
LRRK2
MCOLN1
SCARB2
SLC17A5
SMPD1
Autophagy TMEM175
Mitochondrial function
and maintenance
Lysosomal
function
Variants
ts in
KAT1

(Caption appears on following page)

www.annualreviews.org • Parkinson’s Genetics and Pathophysiology 97

Figure 1 (Figure appears on preceding page)
Parkinson’s disease (PD) pathogenesis involves vesicular trafficking and lysosomal and mitochondrial maintenance. This diagram
summarizes what is currently known about PD genetics. α-Synuclein is shown in the center to highlight its importance and influence in
all known signaling nodes of PD pathogenesis (mitochondrial function, vesicular trafficking, and lysosomal function).

2010). At the trans-Golgi network, LRRK2 is recruited along with GAK (which is encoded by
GAK, another PD risk gene) and promotes the clearance of Golgi-associated vesicles (Roosen &
Cookson 2016).
Recent studies have identified the retromer as having pathophysiological importance in PD.
Two genes associated with retromer function have been linked to PD: VPS35 and PLA2G6. As
mentioned previously, VPS35 is the largest subunit of the complex, and patients with mutations in
its gene have autosomal dominant PD (Vilariño-Güell et al. 2011, Williams et al. 2017, Zimprich
et al. 2011). The mechanism by which VPS35 causes disease remains unclear, with the prevail-
ing hypothesis being that mutations in VPS35 cause retromer dysfunction, which disrupts the
trafficking of lysosomal enzymes and substrates to the lysosome (Williams et al. 2017).
Mutations in PLA2G6 (PARK14) cause a heritable form of dystonia-parkinsonism (Paisán-Ruíz
et al. 2009). PLAG26 codes for phospholipase A2 (PLA2), a calcium-independent phospholipase
whose dysfunction causes the accumulation of ceramides and subsequent retromer dysfunction.
Additionally, PLA2 protein interacts with VPS35 and VPS26 (Lin et al. 2018). Taken together,
mutations in VPS35 and PLA2G6 cause monogenic forms of parkinsonism and are associated
with retromer dysfunction. When the retromer is compromised, lysosomal function is also com-
promised, which may lead to α-syn accumulation.

The Lysosome
α-Syn is mainly degraded by the lysosomal degradation pathway. Specifically, α-syn has been re-
ported to be degraded by the chaperone-mediated pathway (Cuervo et al. 2004) and by macroau-
tophagy (Vogiatzi et al. 2008). This could explain why a large number of genes that function in
the lysosome are also implicated in PD pathogenesis, chief among them being GBA.
GBA mutations lead to an increase in monomeric and oligomeric species of α-syn in human
dopaminergic neurons derived from GD patients as well as in the brains of GD mouse models.
GCase loss-of-function can potentiate neuronal vulnerability to α-syn toxicity by impairing the
lysosome (Henderson et al. 2020) and by exposing α-syn to GluCer, which may promote its ag-
gregation. α-Syn aggregation causes ER stress and stops the trafficking of GCase to the lysosome,
which causes a bidirectional toxic loop in carriers of GBA mutations (Mazzulli et al. 2011). This
finding is in agreement with the observation that peripheral mononuclear cells of PD patients
carrying GBA or SNCA mutations have reduced GCase levels (Papagiannakis et al. 2015), and
reduced GCase activity has been found in PD and GD-PD brains (Chiasserini et al. 2015). In
contrast, some variants cause GCase to misfold, and another hypothesis suggests that this could
influence α-syn accumulation via a gain-of-function (Sidransky & Lopez 2012). It is also possible
that the nature of the mechanism could differ between variants.
If GCase is important for PD pathogenesis, then variants in factors that regulate GCase func-
tion should also modify disease risk. Recently, SNPs in SCARB2, the gene that codes for LIMP-2
(the key protein in GCase trafficking), have been found to increase PD and DLB risk (Bras et al.
2014, Do et al. 2011, Hopfner et al. 2013, Michelakakis et al. 2012, Nalls et al. 2019, Stojkovska
et al. 2018). Notably, Scarb2−/− mice have lysosomal defects and α-syn accumulation (Rothaug
et al. 2014). Additionally, α-syn accumulation has also been shown to cause the dysregulation of
trafficking of key regulators of the lysosomal pathway (Cooper et al. 2006, Mazzulli et al. 2016),
which further promotes this bidirectional loop.

98 Vázquez-Vélez • Zoghbi
 Mutations in other lysosomal genes have also been associated with α-syn accumulation and
PD. ATP13A2 (PARK9) is an ATP-dependent cation transporter required for normal lysosomal
function. It has been previously shown that variants in this gene compromise lysosome function
and thus lead to α-syn accumulation (Ramirez et al. 2006, Schultheis et al. 2013, Tsunemi & Krainc
2014). Additionally, SNPs and rare variants affecting several genes involved in lysosomal function
increase PD risk or are associated with LB presence postmortem. These include genes coding
for lysosomal enzymes (GBA, CTSB, SMPD, GALC, ASAH1), proteins that transport lysosomal
enzymes (SCARB2), lysosomal transmembrane channels (TMEM175, MCOLN1), transporters of
lysosomal substrates (SLC17A5), and proteins involved in autophagy (KAT8) (Billingsley et al.
2018, Hopfner et al. 2013, Krohn et al. 2020b, Robak et al. 2017).
LRRK2 also affects lysosomal function. Although Lrrk2−/− mice lack neurological phenotypes,
they develop kidney and lung phenotypes due to lysosomal dysfunction. (Araki et al. 2018, Herzig
et al. 2011, Miklavc et al. 2014). Other studies in patient neurons have shown that lysosomal defects
caused by LRRK2 dysfunction can affect α-syn protein clearance (Eguchi et al. 2018, Roosen &
Cookson 2016) and that under conditions of stress, Rab7L1 recruits LRRK2 to lysosomes, where
it phosphorylates Rab8/10 to promote clearance of lysosomal contents. Thus, it is possible that by
controlling vesicular and lysosomal function, LRRK2 may also contribute to α-syn accumulation.

The Mitochondria
The third node of signaling is mitochondrial maintenance. Many environmental risk factors for
PD (pesticides, herbicides, solvents, MPTP, etc.) fit into this node. Rotenone is a Complex I in-
hibitor, which compromises the mitochondrial electrochemical gradient and causes dopaminergic
neurodegeneration. Importantly, there is evidence from mouse models that rotenone exposure
increases α-syn levels and phosphorylation (Betarbet et al. 2006, Di Maio et al. 2016). The mech-
anism by which this happens is unclear, but it suggests that α-syn levels may be influenced by
mitochondrial stress. Conversely, α-syn has deleterious effects on mitochondrial health. Studies
in cells, neurons, and mouse brains have found that overexpressed α-syn causes mitochondrial
fragmentation and reactive oxygen species generation (Di Maio et al. 2016, Nakamura et al. 2011).
Some proposed mechanisms include (a) α-syn-mediated inhibition of Complex 1 (Devi et al. 2008);
(b) binding of the mitochondrial transporter TOM20, which inhibits the transport of mitochon-
drial proteins (Di Maio et al. 2016); and (c) binding of the mitochondria-associated membranes
of the ER and, through dysregulation of OPA1, induction of excessive mitochondrial fission
(Guardia-Laguarta et al. 2013). Despite the discrepancies in the proposed mechanisms, it is clear
than an excess of α-syn can negatively influence mitochondria and that mitochondrial dysfunction
can also cause an excess of α-syn, potentially establishing another bidirectional toxic loop.
Mutations in several mitochondrial genes (PARKN, PINK1, FBXO7, PARK7, and VPS13C)
result in ARJP. Although ARJP represents a distinct clinical entity, it shares the mitochondrial
pathway as a commonality with PD. As mentioned previously, the PINK1/Parkin axis regulates
mitochondrial health and turnover. Healthy mitochondria maintain a transmembrane potential
difference, which allows PINK1 to be imported to the inner mitochondrial membrane where it
is proteasomally degraded. When mitochondria are damaged, the mitochondrial chemoelectrical
gradient is lost, and PINK1 accumulates on the outer mitochondrial membrane (OMM). This
allows PINK1 to phosphorylate, recruit, and activate Parkin (Kane et al. 2014, Narendra et al.
2008). Parkin then ubiquitinates multiple OMM proteins, which prevents fusion of damaged mi-
tochondria as well as transport of proteins into damaged mitochondria (Pickrell & Youle 2015).
All of these new ubiquitins can then be phosphorylated by PINK1, initiating a positive feedback
loop. Finally, the increase of pS65 Ub chains on the mitochondria recruits the autophagosome
machinery to degrade the damaged mitochondria (Narendra et al. 2008, Pickrell & Youle 2015).
www.annualreviews.org • Parkinson’s Genetics and Pathophysiology 99
 FBXO7 is required for Parkin recruitment to mitochondria ( Joseph et al. 2018), and loss of
VPS13C leads to an increase in PINK1/Parkin-mediated mitophagy (Lesage et al. 2016). PARK7
codes for DJ-1, a protein that serves various roles in the mitochondria. These roles include acting
as a reactive oxygen species sensor/scavenger, protease, transcriptional regulator, and RNA bind-
ing protein (Dolgacheva et al. 2019). In addition to these genes, some of the genes with SNPs
associated with PD risk (MCCC1, COQ7, and ALAS1) also regulate mitochondrial health.
There are also reports of mitochondrial functions of LRRK2. Namely, LRRK2 can regulate
uncoupling proteins, H2 O2 scavengers, and regulators of translation under mitochondrial stress
(Haelterman et al. 2014). Thus, LRRK2 function integrates all three susceptibility nodes of PD
pathogenesis, and at all three nodes it can feed into α-syn accumulation.

Other Pathways
Apart from these three nodes, there are other less well-characterized pathways that may contribute
to PD pathogenesis. For example, there is a potential role for α-syn in the nucleus. First, the G51D
mutation of α-syn drives it to the nucleus and causes familial PD (Fares et al. 2014). Second,
TRIM28, a regulator of α-syn levels, promotes its nuclear localization (Rousseaux et al. 2016).
And third, a recent study suggests that α-syn may be normally involved in DNA damage repair
(Schaser et al. 2019).
It is also worth noting that there are non-cell-autonomous contributions to PD pathophysiol-
ogy. For example, T cell infiltration has been found in postmortem PD brains, SNPs near HLA
genes are associated with increased PD risk, LRRK2 regulates inflammation, α-syn has been pro-
posed to have antimicrobial properties, and α-syn aggregates have been reported to induce mi-
croglial activation. Therefore, it is likely that neuroinflammation plays a role in PD pathophys-
iology (Caggiu et al. 2019, Chang et al. 2017). The question that remains is whether this role is
upstream or downstream of the cell-autonomous mechanisms described here.

Harnessing Parkinson’s Disease Pathophysiology to Develop

Disease-Modifying Treatments
Degeneration of dopaminergic neurons causes parkinsonian motor symptoms. However, distin-
guishing between different causes of parkinsonian symptoms will be essential for developing ef-
fective treatments. For example, it is now clear that ARJP can be considered a distinct patho-
physiological entity from PD. This is because ARJP patients have pathology that is limited to the
substantia nigra, and PARKN variants are not associated with PD. Thus, specific therapeutics for
PARKN- and PINK1-driven disease will have to be developed. As more is learned about atypical
PD syndromes, it is likely that these too may be considered distinct clinical entities.
We hypothesize that the clinical entity of PD is a collection of diseases with partially overlap-
ping pathophysiologic mechanisms, with a common thread of α-syn accumulation in LBs. Thus,
it follows that there are multiple avenues that can be used to target specific mechanisms in people
with familial disease, and that targeting α-syn itself will be beneficial in idiopathic and familial
disease.
To target LRRK2 variant–driven PD, there are various LRRK2 kinase inhibitors currently in
clinical trials (Alessi & Sammler 2018, Dawson & Dawson 2019). Molecular chaperones that in-
crease mutant GCase trafficking to the lysosome and small molecules that reduce glucocerebroside
production are being pursued to target GBA variant–driven PD (Dawson & Dawson 2019, Wong
& Krainc 2017). If successful in their subtypes, these drugs should then be tested in idiopathic PD
cases, as there are potential links between LRRK2, GCase, and α-syn.

100 Vázquez-Vélez • Zoghbi

 There are several approaches aimed at reducing α-syn levels, aggregation, and spreading.
These include antisense oligonucleotides and monoclonal antibodies (Cole et al. 2019, Dawson &
Dawson 2019). Additionally, our group and others have chosen the identification of proteins
that modify α-syn levels and accumulation as a therapeutic approach (Brahmachari et al. 2016,
Rousseaux & Vázquez-Vélez et al. 2018, Rousseaux et al. 2016, Vázquez-Vélez et al. 2020). Us-
ing our knowledge of the molecular pathophysiology of PD will help guide the development of
disease-modifying therapies and will clarify the roles of these pathways in disease.

DISCLOSURE STATEMENT
H.Y.Z. is on the Board of Regeneron and the Scientific Advisory Board of The Column Group,
is a co-founder of Cajal Neuroscience, and collaborates with UCB Pharmaceuticals and Ionis
Pharmaceuticals.

ACKNOWLEDGMENTS
The authors would like to thank Laurie A. Robak and Joshua M. Shulman for their critiques and
helpful comments on this manuscript.

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