NEURODEGENERATIVE DISORDERS

Parkinson’s Disease
• Caused by degeneration of the nigrostriatal system (dopamine-secreting neurons of the substantia nigra that send axons
to the basal ganglia)
• Occurs in approx. 1% of people over 65 years of age
• Symptoms: muscular rigidity, slowness of movement, a resting tremor, and postural instability
o Reaching for an object can be accurate, but the movement usually begins only after a considerable delay
o Writing s slow and labored, and as it progresses, the letters get smaller and smaller
o Motor deficits can be described as a deficiency of automatic, habitual responses caused by damage to the basal ganglia
• Produces resting tremor – vibratory movements of the arms and hands that diminish somewhat when the individual makes
purposeful movements
o Accompanied by rigidity; joints appear stiff
o Tremor and rigidity are not the cause of the slow movements
• Near-disappearance of nigrostriatal dopaminergic neurons
o Many surviving dopaminergic neurons show Lewy bodies, abnormal circular structures found within the cytoplasm
§ Lewy bodies have a dense protein core, surrounded by a halo of radiating fibers
• Akinesia (difficulty in initiating movements) was associated with decreased activation of the supplementary motor area
and that tremors are associated with abnormalities of a neural system involving the pons, midbrain, cerebellum, and
thalamus
Causes
• Mutation of a particular gene located on chromosome 4
o This gene produces a protein known as α-synuclein, which is normally found in the presynaptic terminals and is thought
to be involved in synaptic transmission in dopaminergic neurons
o Mutation produces toxic gain of function
§ Produces a protein that results in effects that are toxic to the cell
o Abnormal α-synuclein becomes misfolded and forms aggregations, especially in dopaminergic neurons
§ Dense core of Lewy bodies consists primarily of these aggregations, along with neurofilaments and synaptic vesicle
proteins
• Mutation of a gene on chromosome 6 à produces a gene called parkin
o Causes loss of function (makes it a recessive disorder)
§ If a person carries a mutated parkin gene on only one chromosome, the normal allele on the
other chromosome can produce a sufficient amount of normal parkin for normal cellular
functioning, and the person will not develop Parkinson’s disease
o Normal parkin plays a role in transferring defective or misfolded proteins to the proteasomes—
organelles responsible for destroying these proteins
o Mutation permits high levels of defective protein to accumulate in dopaminergic neurons and
ultimately damage them
• Ubiquitination: tagging of abnormal or misfolded proteins with molecules of ubiquitin (a small, compact globular protein)
by parkin; targets abnormal proteins for destruction by the proteasomes, which break them down into their constituent
amino acids
o Defective parkin fails to ubiquinate abnormal proteins, and they accumulate in the cell, eventually killing it
o Dopaminergic neurons are especially sensitive to this accumulation
• Approximately 95% of cases are sporadic (occurs in people without a family history of PD)
• May be caused by toxins present in the environment, by faulty metabolism, or by unrecognized infectious disorders
o E.g. insecticides rotenone and paraquat
o Inhibits mitochondrial function à aggregation of misfolded α-synuclein, especially in dopaminergic neurons à
accumulated proteins kill the cells
• 2 major systems of dopaminergic neurons
o Nigrostriatal system: damage in this system causes PD
o Mesolimbic/mesocortical system: consists of dopaminergic neurons in the ventral tegmental area that innervate the
nucleus accumbens and the prefrontal cortex
• Calcium channels are involved in regulating the spontaneous activity of DA cells in the nigrostriatal system; sodium
channels are involved in regulating the activity in mesolimbic/mesocortical system
 o Presence of α-synuclein, elevated intracellular calcium ions, and elevated levels of intracellular dopamine combine to
kill these cells
o Interference with any of these three factors prevents damage to these cells
§ Because DA neurons of the mesolimbic/mesocortical system do not contain elevated levels of calcium ions, they are
spared
Treatments
• There is no cure for PD; there are just pharmacological and surgical interventions options to treat the symptoms
Drug Treatments
• L-DOPA: precursor of dopamine
o Increased level of L-DOPA in the brain causes the remaining dopaminergic neurons to produce and secrete more
dopamine and, for a time, alleviates the symptoms of the disease
o Eventually, the number of nigrostriatal dopaminergic neurons declines to such a low level that the symptoms become
worse
o Also activates DA neurons in the mesolimbic/mesocortical system and produces side effects such as hallucinations and
delusions
• Deprenyl: inhibits the activity of enzyme MAO-B; usually given in conjunction to L-DOPA
o Toxic effects of an illicit drug contaminated with MPTP (taken by people who later acquired the symptoms of PD) could
be prevented by deprenyl
o Might prevent unknown toxins from producing further damage to dopaminergic neurons
o Does no slows down the degeneration of dopaminergic neurons
• Transplantation of fetal tissue
o Attempts to reestablish the secretion of dopamine in the neostriatum
o Tissue is obtained from the substantia nigra of aborted human fetuses and implanted into the caudate nucleus and
putamen using stereotaxically guided needles
o Dopaminergic fetal cells are able to grow in their new host and secrete dopamine, reducing the patient’s symptoms
o Many transplant patients later developed severe dyskinesias – troublesome and often painful involuntary movements
o Cells eventually develop deposits of α-synuclein
§ Misfolded α-synuclein is transferred from the recipient’s own neurons to the grafted neurons
§ Misfolded proteins responsible for several neurodegenerative diseases can be transferred from cell to cell in the
brain where they induce further protein misfolding
Surgical Procedures
• The principal output of the basal ganglia comes from the internal division of the
globus pallidus (GPi)
o The output, which is directed through the subthalamic nucleus (STN) to the motor
cortex, is inhibitory
• A decrease in the activity of the dopaminergic input to the caudate nucleus and
putamen causes an increase in the activity of the GPi
o Damage to the GPi might be expected to relieve the symptoms of PD
• 1950s: Leksell et al. performed pallidotomies (surgical destruction of the internal
division of the globus pallidus) in patients with severe PD
o Surgery reduced the rigidity and enhanced the patient’s ability to move
o Also occasionally made the patient’s symptoms worse and sometimes resulted in
partial blindness. (The optic tract is located next to the GPi)
o Pallidotomies were abandoned in the 1960s when L-DOPA therapy was developed
• 1990s: began experimenting again with pallidotomies
o Used MRI scans to find the location of GPi, and then inserted an electrode into the target region
o Surgeon would pass radiofrequency current to heat and destroy the brain tissue
• Targeted the subthalamic nucleus in patients with advanced PD
o STN has an excitatory effect on the GPi
§ Damage to the STN decreases the activity of this region and removes some of the inhibition on motor output
o Result: brings depressed motor activity back to normal
• Optogenic methods: used to stimulate or inhibit specific types on neurons in specific locations of the brain
o Kravitz et al. used a genetically engineered virus to insert into mice light- sensitive proteins in the neurons of the
striatum that receive inputs from axons of dopaminergic neurons of the substantia nigra
 § Used 2 different procedures that enabled them to stimulate neurons that contained either
dopamine D1 receptors (part of the direct pathway of the cortical–basal ganglia loop) or
dopamine D2 receptors (part of the indirect pathway)
• Activation of direct pathway (inhibits GPi) à symptoms disappeared
• Activation of indirect pathway (excites GPi) à mice displayed motor symptoms seen in PD
§ Motor symptoms of PD are produced by a shift of balance in favor of the indirect pathway
• Deep brain stimulation (DBS): implanting electrodes in the STN or the GPi and attaching a device that
permits the patient to electrically stimulate the brain through the electrodes
o Effective in suppressing tremors and has fewer adverse side effects
o Has an inhibitory effect on STN neurons
§ By causing more complex changes in the firing of particular neurons in the STN by activating
axons that enter this structure
• Kaplitt et al: introduced a genetically modified virus into the subthalamic nucleus of patients with
Parkinson’s disease that delivered a gene for GAD (enzyme responsible for the biosynthesis of GABA)
o Production of GAD turned some of the excitatory, glutamate-producing neurons in the subthalamic
nucleus into inhibitory, GABA- producing neurons
o Result: activity of the GPi decreased, activity of the supplementary motor area increased, and the
symptoms of the patients improved

Huntington’s Disease
• Caused by the degeneration of the caudate nucleus and putamen
• Causes uncontrollable, jerky limb movements
o Movements look like fragments of purposeful movements but occur involuntarily
• Progressive; includes cognitive and emotional changes, and eventually causes death, usually within 10–15
years after the symptoms begin
• Symptoms usually begin in the 30s and 40s but can sometimes begin in the early 20s
• First signs of neural degeneration occur in the putamen, in a specific group of inhibitory neurons:
GABAergic medium spiny neurons
o Damage removes some inhibitory control exerted on the premotor and supplementary motor areas of
the frontal cortex à involuntary movements
• As the disease progresses, neural degeneration is seen in many other regions of the brain, including the cerebral cortex
Causes
• Hereditary; caused by a dominant gene on chromosome 4
• Defect: repeated sequence of bases (called CAG repeats) that code for the
amino acid glutamine
o Causes the gene product—a protein called huntingtin (Htt)—to contain
an elongated stretch of glutamine
o Abnormal Htt becomes misfolded à forms aggregations that accumulate
in the nucleus
o Mutation causes the disease through a toxic gain of function
• Cause of death of neurons is apoptosis (cell suicide)
o Abnormal Htt may trigger apoptosis by impairing the function of the ubiquitin- protease system, which activates
caspase, one of the enzymes involved in apoptosis
• Accumulation of misfolded Htt in the nucleus (inclusion bodies) have a protective function
o Neurons that contained inclusion bodies had lower levels of mutant Htt elsewhere in the cell, and these neurons lived
longer than those without these accumulations

Treatments
• No treatment for Huntington’s disease
• Special type of antibody that acts intracellularly (an intrabody) called Happ1
o Targets a portion of the huntingtin protein
o Insertion of Happ1 gene into the animals’ brains suppressed production of mutant Htt and improved the animal’s
disease symptoms
• Injection of small interfering RNAs (siRNA) into the striatum that blocked the transcription of the Htt genes—and hence the
production of mutant Htt protein— in this region
 o Decreased the size of inclusion bodies in striatal neurons, prolonged the life of the striatal neurons, and reduced the
animals’ motor symptoms

Amyotrophic Lateral Sclerosis

• Attacks the spinal cord and cranial nerve motor neurons
• Incidence: 5 in 100,000
• Symptoms: spasticity (increased tension of muscles, causing stiff and awkward movements), exaggerated stretch reflexes,
progressive weakness and muscular atrophy, and, paralysis
• Muscles that control eye movements are spared
• Some cognitive abilities (e.g. executive function, working-memory, language social cognition) may also be affected
• Death usually occurs 5–10 years after the onset of the disease as a result of failure of respiratory muscles
Causes
• 10% of cases are hereditary
o 10-20% are caused by a mutation in the gene that produces the enzyme superoxide dismutase 1 (SOD1), found on
chromosome 21
§ Mutation causes a toxic gain of function that leads to protein misfolding and aggregation, impaired axonal transport,
and mitochondrial dysfunction
§ Impairs glutamate reuptake into glial cells à increases extracellular levels of glutamate and causes excitotoxicity in
motor neurons
o Mutant SOD1 can be transmitted from cell to cell
o SOD1 normally functions as a detoxifying enzyme found in the cytoplasm and mitochondria
§ Converts superoxide radicals to molecular oxygen and hydrogen peroxide
• 90% are sporadic
o Primary cause: abnormality in RNA editing
§ Faulty editing of mRNA that codes for a particular glutamate receptor subunit (GluR2) in motor neurons results in
the production of glutamate AMPA receptors that admit increased amounts of calcium ions into these neurons
§ Excess intracellular calcium contributes to apoptosis, and a result, the cells die from excitoxicity
Treatments
• Riluzole: drug that reduces glutamate-induced excitotoxicity, probably by decreasing the release of glutamate

Multiple Sclerosis
• Autoimmune demyelinating disease
• At scattered locations within the central nervous system, the person’s immune system attacks myelin sheaths, leaving
behind hard patches of debris called sclerotic plaques
• Normal transmission of neural messages through the demyelinated axons is interrupted
• Damage occurs in white matter located throughout the brain and spinal cord
• Remitting-relapsing MS: symptoms often appear, increase in intensity and then decrease, to be followed by an- other
increase in symptoms after varying periods of time
o Often followed by progressive MS later in the course of the disease
• Progressive MS: slow, continuous increase in the symptoms of the disease
Causes
• Afflicts women more frequently than men; occurs in people in their late 20s or 30s
• People who spend their childhood in places far from the equator are more likely to be diagnosed with the disease than are
those who live close to the equator
o It is likely that some disease contracted during a childhood spent in a region in which the virus is prevalent causes the
person’s immune system to attack his or her own myelin
o Virus weakens the blood–brain barrier, allowing myelin protein into the general circulation and sensitizing the immune
system to it, or; the virus attaches itself to myelin
• People born during the late winter and early spring are at higher risk
Treatments
• Interferon β: protein that modulates the responsiveness of the immune system
o Reduces frequency and severity of attacks and to slow the progression of neurological disabilities
o Treatment is only partially effective
• Glatiramer acetate (copaxone or copolymer-1): mixture of synthetic peptides composed from random sequences of the
amino acids tyrosine, glutamate, alanine, and lysine
 o First produced in an attempt to induce the symptoms of MS in lab animals, but it turned out to actually reduce them
• Interferon β and glatiramer acetate are effective only for the remitting-relapsing and not the progressive form of MS
• Experimental allergic encephalitis (EAE): experimentally induced demyelinating disease; can be produced in lab animals by
injecting them with protein found in myelin
o Immune system then becomes sensitized to myelin protein and attacks the animal’s own myelin sheaths
• Glatiramer acetate prevented EAE, stimulating certain cells of the immune system to secrete anti-inflammatory chemicals
such as interleukin 4 (suppress activity of immune cells that would otherwise attack the patient’s myelin)
• BG-12: new drug that may be effective in reducing the number of brain lesions, the rate of relapse, and the rate of
disability progression in relapsing MS
• Transplantation of autologous hemopoietic stem cells: transplants of adult stem cells taken from a patient’s own blood or
bone marrow

Dementia
• Deterioration of intellectual abilities resulting from an organic brain disorder
• Presence of Lewy bodies in up to 20% of patients diagnosed with dementia
• Most common form Alzheimer’s disease
o Occurs in approximately 10% if population above the age of 65 and almost 50% of
people older than 85
o Progressive loss of memory and other cognitive functions
o Memory deficit most critically involves recent events
o Produces severe degeneration of the hippocampus, entorhinal cortex, neocortex (especially the association cortex of
the frontal and temporal lobes), nucleus basalis, locus coeruleus, and raphe nuclei
• Brain: much wider sulci, especially in the frontal and temporal lobes, indicating substantial loss of cortical tissue
• Amyloid plaques: extracellular deposits that consist of a dense core of a protein known as β-amyloid, surrounded by
degenerating axons and dendrites, along with activated microglia and reactive astrocytes, cells
that are involved in destruction of damaged cells
o Phagocytic glial cells destroy the degenerating axons and dendrites, leaving only a core of β-
amyloid (usually referred to as Aβ)
o Formation is caused by the production of a defective form of Aβ
o Production of Aβ
§ A gene encodes the production of the β-amyloid precursor protein (APP), a chain of
approximately 700 amino acids
§ APP is cut apart in 2 places by enzymes called secretases to produce Aβ
• β-secretase, cuts the “tail” off of an APP molecule
• γ-secretase (gamma-secretase), cuts the “head” off
§ Result: molecule of Aβ that contains either 40 or 42 amino acids
o Location of the second cut of the APP molecule by γ-secretase determines which form is
produced
§ Healthy brains: 90-95% of the Aβ molecules are of the short form; the other 5–10 percent are of the long form
§ Patients with AD: proportion of long Aβ rises to 40%
• Tendency to fold themselves improperly and form aggregations
• Neurofibrillary tangles: dying neurons that contain intracellular accumulations of twisted filaments of
hyperphosphorylated tau protein
o Normal tau protein: component of microtubules, which provide the cells’ transport mechanism
o Excessive amounts of phosphate ions become attached to strands of tau protein, thus changing the molecular structure
• Acetylcholinergic neurons in the basal forebrain are among the first cells to be affected in AD
• Aβ serves as a ligand for the p75 neurotrophic receptor, a receptor that normally responds to stress signals and stimulates
apoptosis
o Basal forebrain Ach neurons contain high levels of these receptors
§ Once the level of long-form Aβ reach a sufficiently high level, these neurons begin to die
• Frontotemporal dementia (Pick’s disease): causes degeneration of the frontal and temporal cortex, resulting in emotional
changes and loss of executive functions caused by damage to the prefrontal cortex and language disturbance caused by
temporal lobe damage
o From the mutations in the gene for tau protein (found on chromosome 17) that produces neurofibrillary tangles
• Presence of excessive amounts of Aβ in the cytoplasm of cells, not the formation of extracellular amyloid plaques, is the
cause of neural degeneration
• Intracellular oligomers of Aβ (aggregations of several Aβ molecules) activate microglia, causing an inflammatory response
that triggers the release of toxic cytokine (chemicals produced by the immune system that normally destroy infected cells)
o Also trigger excessive release of glutamate by glial cells à excessive inflow of calcium ions through neural NMDA
receptors à excitotoxicity
o Cause synaptic dysfunction and suppress the formation of long-term potentiation
Causes
• Hereditary; chromosome 21 contains gene that produces APP
• Numerous mutations of two presenilin genes, found on chromosomes 1 and 14, produce Alzheimer’s disease
o PS1 and PS1 are subunits of γ-secretase
• Abnormal APP and presenilin genes all cause the defective long form of Aβ to be produced
• Apolipoprotein E (ApoE): glycoprotein that transports cholesterol in the blood and also plays a role in cellular repair
o E4, one allele of ApoE gene, increases the risk of late-onset Alzheimer’s disease, apparently by interfering with the
removal of the long form of Aβ from the extracellular space in the brain
o ApoE2 allele may protect people from AD
• Traumatic brain injury is also a risk factor for AD
o Especially high for those who possess ApoE4 allele
o Strongest known nongenetic risk factor
• Obesity, hypertension, high cholesterol levels, and diabetes are also risk factors and are exacerbated by the presence of
the ApoE4 allele
• Positive relationship between increased number of years of formal education and cognitive performance, even in people
whose brains contained significant concentrations of amyloid plaques
o Formal education appears to enable a person to maintain a higher level of cognitive performance even in the face of
brain degeneration
Treatments
• Acetylcholinesterase inhibitors: donepezil, rivastigmine, and galantamine
o Provide a modest increase in cognitive measures
o Have no effect on the process of neural degeneration and do not prolong patients’ surviva;
• NMDA receptor agonist: memantine
o Produces slight improvement in symptoms of dementia by slowing excitotoxic destruction of acetylcholinergic neurons
caused by the entry of excessive amounts of calcium
• Vaccine that would stimulate the immune system to destroy Aβ
o To sensitize the immune system against Aβ
o Suppressed development of amyloid plaques
o Antibody production significantly reduced cognitive decline
o However, it caused an inflammatory reaction in the brains of 5% of patients
• New approach involving aducanumab (replica of a naturally-occuring protective antibody that recognizes Aβ oligomers)