Parkinson disease Huntington disease Flashcards
Basal Ganglia
disorders (PD and HD)
The basal ganglia are islands of gray matter
embedded in the subcortical white matter. Texts vary
on what they include but most agree on at least:
Caudate, Putamen, Globus pallidus (interna and
externa), and Subthalamic nucleus
Basal Ganglia Disorders
v Hypokinetic Disorders
* Parkinson’s disease
* Dementia with Lewy bodies
* Progressive Supranuclear Palsy
* Corticobasal Syndrome
* Multiple System Atrophy
v Hyperkinetic Disorders
* Huntington’s disease
* Essential Tremor
* Dystonia
* Restless Leg Syndrome
* Tics and Tourette syndrome
* Attention-deficit/hyperactivity disorder
Basal Ganglia
circuitry in health and disease
The primary function of the basal ganglia is to provide a
feedback mechanism to the cerebral cortex for the initiation
and control of motor responses. Much of the basal ganglia
output, all of which mediated through the thalamus, is to
reduce or dampen the excitatory input to the cerebral
cortex. When there is a disruption of this mechanism,
disturbances in motor function ensue.
When the discharge patterns of the basal ganglia become
excessive, the effect on motor systems is to produce
abnormal slowing of movements (akinesia or bradykinesia,
as in PD). At other times, however, lesions of the basal
ganglia produce a reduced output, the result of which is the
presence of abnormal, involuntary movements that occur
during rest (dyskinesia and hyperkinesia, as in HD and
Dystonia).
MSN: medium spiny neurons;
dMSN: MSN in the direct pathway
iMSN: MSN in the indirect pathway
SNr: Substantia nigra pars reticulata
GPe: Globus pallidus pars externa
GPi: Globus pallidus pars interna
STN: Subthalamic nucleus
SNc: Substantia nigra pars compacta
Parkinson’s disease
History and Epidemiology
- History: First described in a 1817 article (“An essay on the
Shaking Palsy”) by British physician James Parkinson. Later
French physician JM Charcot described it broadly and
importantly noted, muscle weakness in PD is not due to defects
in muscles but something out-of-order in the brain. - The proteinaceous inclusion bodies, now called Lewy bodies
and known to be pathological hallmark of PD, were shown in
1912 by Frederick Lewy. - In 1950s, the role of dopamine in PD was revealed. Blocking
dopamine uptake with uptake-inhibitor reserpine produced PD-
like symptoms in rabbits (shown by Swedish Arvid Carlsson). - Carlson also reversed the symptoms by giving them dopamine
precursor L-DOPA. - In 1967, L-DOPA was approved for treatment of PD. Levodopa,
which is L-DOPA plus a decarbolxylase inhibitor–carbidopa–that
prevents systemic dopamine conversion of L-DOPA, is the
standard treatment today. - Levodopa is very effective during early stages of PD, but the
effect is short-lived in advanced stages of the diseases. It
doesn’t eliminate the cause and therefore the progression of
the disease
PD stats
- After AD, PD is the second-leading neurodegenerative disorder,
affecting about 1 million people in the US and six million people
globally. - Incidence increases 5- to 10-fold from the sixth to the ninth decades of
life. (PD prevalence increases with age). - In a meta-analysis of four North American populations, prevalence
increased from less than 1 percent of men and women aged 45–54
years to 4 percent of men and 2 percent of women aged 85 or older. - As the global population ages, PD prevalence is expected to increase
dramatically, doubling in the next two decades.
Parkinson’s disease
The neurodegenerative process
The neurodegenerative process in Parkinson’s disease
initially targets and predominantly affects the ventrolateral
tier of the substantia nigra pars compacta, which projects
to the caudal (posterior) putamen, where dopamine deficit
begins and is most severe.
Lewy bodies: PD patients show intracellular protein
aggregates in their brains, called Lewy bodies. LB
pathologies include Parkinson’s disease (PD), Parkinson’s
disease dementia (PDD), and dementia with Lewy bodies
(DLB). Made of misfolded a-synuclein.
Are Lewy bodies contributors to the disease progression
or are an irrelevant byproduct of the disease process? Not
conclusively known yet. But Lewy bodies, or at least the a-
synuclein contained in them could be disease causing.
Concomitant pathologies: Many patients have co-deposits
of AD pathologies. This could explain the development of
cognitive deficit found only in a fraction of PD patients.
Role of a-Syn
a-Syn is a small 140 aa-long intrinsically disordered
protein that is primarily found in nerve terminals
where it binds with the synaptic vesicle(SV)
membrane through the N-terminal lipid-binding
domain. Upon binding, the natively unfolded protein
adopts an a-helical conformation and promotes
SNARE-dependent complex formation during the
process of vesicular trafficking including SV
clustering, docking and priming, which eventually
leads to neurotransmitter release at the synaptic
junction.
During PD, a-Syn can aggregate as fibrils due to
misfolding and also undergo LLPS in a crowded
environment, which gradually undergo an
irreversible liquid-to-solid phase transition into
amyloid-like hydrogel entrapping oligomers and
fibrils, which eventually end up as Lewy bod
Genetics of PD
Several years of genetic research in
Parkinson’s disease (PD) have led to the
identification of several monogenic forms of
the disorder and of numerous genetic risk
factors increasing the risk to develop PD.
Monogenic forms, caused by a single
mutation in a dominantly or recessively
inherited gene, are well-established, albeit
relatively rare types of PD. They collectively
account for about 30% of the familial and 3%–
5% of the sporadic cases.
Early Onset PD: age of onset ≤50 yr. E.g.,
SNCA (codes for a-Syn), PINK1, Parkin, etc.
Mutations in the LRRK2 gene are the most
frequent known cause of late-onset
autosomal-dominant and sporadic PD. Role of
LRRK2 protein, a kinase, remains enigmati
Deep Brain
Stimulation
Levodopa induces dyskinesia in advanced
stages of PD, which is why many patients stop
taking it.
Surgery is often reserved for those who have
optimized and exhausted medications for
Parkinson’s tremor, or who experience
profound motor fluctuations.
Currently, the two most common surgical
treatments available for people living with PD
are called deep brain stimulation (DBS) and
Duopa™ (direct delivery of levodopa like
drugs to the intestine).
DBS is surgical placement of an electrode in
subthalamic nucleus (STN) or globus pallidus
internus (GPi) to replenish basal gangliar
circuitry.
HD Pathology
- Huntington’s disease is mainly associated with striatal pathology
(medium spiny GABA neurons) and specific neuronal loss in layers V
and VI of the cerebral cortex, which disrupt neuronal network activity
in several corticobasal ganglia loops. - Patients have dyskinetic movements, behavioral disorders, cognitive
defects, and dementia. - HD is a neurodegenerative disease caused by CAG repeat expansion
in the huntingtin gene (HTT) and involves a complex web of
pathogenic mechanisms. CAG is the triplet code for Glutamine (Q). - In humans, the exon-1 of HTT gene normally contains between 6–35
CAG repeats, whereas in patients affected by HD more than 40
repeats have been described. In most cases, an intermediate number
(36–40) of CAG repeats leads to a slower progression of the pathology
as a result of the incomplete penetrance of the mutant allele. Thus, the
onset and severity of the pathology is directly correlated with the
number of CAG repeats, although the actual function of the
trinucleotide stretch remains unknown. Known to form inclusions. - HD is one of over 40 diseases that are caused by expansion of simple
repeats, most of which, for unknown reasons, primarily affect the
nervous system.
Clinical features of the HD brain: - Enlarged ventricles
- Cell death voids filled with fluids (dark)
- Atrophy of basal ganglia tissue
Cytoplasmic inclusions are different from nuclear inclusions in
displaying a core and shell organization if the polyQ length is
relatively long (72Q) but not if it is close to the pathogenic threshold
(39Q), even if inclusions are still formed in the second case.
Pathogenesis of HD
Mutant HTT can produce multiple toxic variants that
may contribute to HD pathogenesis via:
1) RNA hairpins formed by small CAG-repeated RNAs,
2) abnormal repeat-associated non-ATG (RAN) translation
protein products,
3) proteolysis of HTT to generate smaller fragments,
which can form oligomers or aggregate into large
inclusion bodies.
Pathogenic mechanisms: transcriptional
dysregulation, impaired mitochondrial function,
synaptic dysfunction, endoplasmic reticulum (ER)
stress and loss of trophic support to medium spiny
neurons (MSNs).
MSN excitability and death: mHTT impairs
extracellular ion homeostasis and glutamate uptake
by astrocytes at the synapse by altering the
expression of inwardly rectifying potassium channel
Kir4.1 and glutamate transporter 1 (GLT1), which
can lead to increased MSN excitability and
activation.
Moreover, mHTT can cause aberrant immune
activation in cells of both the peripheral and central
nervous system, resulting in neuroinflammation. The
dysfunction that occurs in multiple vital cellular
processes leads to toxicity over time and neuronal
death.
Therapeutic
approaches in HD
No drugs yet to halt disease progression.
Tetrabenazine, a dopamine depleting agent, is
approved to ameliorate symptoms (chorea).
a | Antisense oligonucleotides (ASOs) bind to
complementary sequences found in HTT precursor
mRNA (pre-mRNA) and mature mRNA to promote
RNase H-mediated degradation of the transcript and
suppress production of mutant huntingtin (mHTT).
b | Artificial small interfering RNAs (siRNAs), short
hairpin RNAs (shRNAs) and microRNAs (miRNAs)
target sequences in HTT mRNA and are processed by
endogenous cellular machinery and incorporated into
the RNA-induced silencing complex (RISC) to promote
silencing of HTT.
c | Zinc-finger proteins that target the expanded CAG
tract can be fused with the transcriptional repressor
domain (for example, the KRAB domain of human zinc-
finger protein KOX1) to prevent transcription of
mutated HTT.
d | ASOs that bind within the HTT exon 12 pre-mRNA
promote exon skipping to omit caspase cleavage sites
and prevent proteolysis of mHTT.
Alternatively, allele-selective silencing can be achieved
by CRISPR technology.
