Download Parkinson’s Disease Genetics

Parkinson’s Disease Genetics
Genomics and Personalized Medicine
5/22/2012
Ryan Bell
Parkinson’s disease (PD)
PD is a chronic, progressive
neurodegenerative disorder.
PD afflicts 1.5 million people in North
America, and over 4 million worldwide.
In 1817, Dr. James
Parkinson published the
first widely
acknowledged
description of
Parkinson’s disease: “An
essay on the shaking
palsy.”
PD is primarily a sporadic disease
affecting people over 60, but many
familial forms have been identified, most
which are early-onset.
Symptoms of PD
•Tremor (usually when limbs are at rest)
•Muscular rigidity (increased resistance
during movement, may be associated with
pain)
•Bradykinesia (slowness of movement
resulting from difficulties with planning,
initiating and executing movement, and
with performing sequential and
simultaneous tasks)
•Postural instability (impaired balance and
coordination, usually a manifestation of late
stage PD)
PD is characterized by protein aggregates and
neuron degeneration
In 1912, Frederick Lewy reported neuronal
cytoplasmic protein inclusions in the midbrain of PD
patients.
In 1919, Konstantin Tretiakoff was the first to link PD
with the abnormal loss of neurons in the substantia
nigra, a part of the basal ganglia.
Dopamine (DA) and PD
In 1957, Arvid Carlsson and colleagues demonstrated that DA was an
abundant neurotransmitter in the basal ganglia.
They subsequently showed that feeding reserpine, which depletes DA in
presynaptic neurons, to animals caused a loss of movement control
similar to PD.
They were able to alleviate these symptoms by administering L-DOPA, the
precursor to DA which can cross the blood-brain barrier. Various forms of
L-DOPA are still the most widely used treatment for the disease.
Causes of PD?
By the 1970s, it was clear that the classic, L-DOPA responsive symptoms
of PD were a consequence of reduced DA levels resulting from DA
neuron degeneration in the substantia nigra.
The causes of the degeneration remained a mystery.
Causes of PD?
In 1982, a group of opiate addicts injected a dose of an illicitly produced
batch of the synthetic opiate MPPP that was contaminated with a
similar compound, MPTP.
Within days, they exhibited permanent symptoms of severe end-stage
PD, most notably akinesia, the inability to initiate movement.
MPTP is a mitochondrial toxin
MPTP was later shown to be selectively toxic to DA neurons because once it enters the
brain, it is converted to MPP+, which has high affinity for the DA transporter used for
DA reuptake in synapses.
Inside DA neurons, MPP+ causes cell death by interfering with the electron transport
chain in mitochondria, which decreases the ATP available to the cells, as well as
causing oxidative stress by generating reactive oxygen species.
Many pesticides are mitochondrial toxins
The similarity of MPP+ to the widely used herbicide paraquat, as well as
epidemiological data suggesting a positive correlation between pesticide
exposure and incidence of PD led to many studies of the effects of pesticides
on DA neurons in animal models.
Paraquat and rotenone, a broad spectrum pesticide which is a mitochondrial
toxin like MPP+, were eventually found to cause PD-like symptoms in animals.
Rotenone
What about the Lewy bodies?
It is now known that Lewy bodies are primarily composed of the
protein α-synuclein, along with ubiquitin and other proteins.
Animal models using paraquat and rotenone display α-synuclein
positive neuronal protein aggregates.
Animal studies using inhibitors of the ubiquitin-proteosome pathway
have also been able to reproduce the hallmark features of PD.
α-synuclein
• α-synuclein is highly abundant in neurons and
associates with membranes and microtubules.
It is thought to have activity similar to tau,
which stabilizes microtubules, and is
implicated in a number of neurodegenerative
disorders, including Alzheimer's disease.
• α-synuclein is also believed to be involved in
vesicle trafficking.
Is dopamine to blame?
• Lewy bodies are found in other types of neurons, but only
dopaminergic neurons die in large numbers in PD.
• Under conditions of oxidative stress and formation of α-synuclein
aggregates, storage of dopamine in synaptic vesicles can be
disrupted, allowing the release of reactive metabolites into the
cytosol, which further exacerbate oxidative stress.
• Dopamine has also been shown to bind and stabilize α-synuclein
protofibrils.
• However, treatment with L-DOPA, which raises dopamine levels,
has not been shown to accelerate disease progression.
Genetic causes of PD
Genes segregating with PD
Proposed protein function
Disease phenotype
Autosomal recessive
Parkin
PINK1
DJ-1
Ubiquitin E3 ligase
Mitochondrial kinase
Oxidative stress protection
Autosomal dominant
UCH-L1
α-synuclein
LRRK2
Ubiquitin hydrolase
Early-onset PD
Microtubule stabilization, vesicle trafficking Early-onset PD
Kinase
Late-onset PD
Juvenile PD
Early-onset PD
Early-onset PD
Of these inherited forms of PD, those caused by mutations in LRRK2 are the most
common, and only they closely match the typical late-onset, as well as clinical and
pathological features of sporadic PD.
LRRK2 is also the most frequently mutated locus in cases of sporadic PD.
LRRK2 (Leucine-rich repeat kinase 2)
It is a member of the Roco protein family, which always possess Roc and COR domains
in tandem.
The Roc domain is a Ras like GTPase, while the COR domain functions as a hinge
between the Ras and kinase domains.
LRRK2 mutations linked to PD
G2385R
The G2019S mutation is dominant, and considered to be
“disease causing,” but has incomplete penetrance.
According to the International LRRK2 Consortium, the
overall PD risk for carriers is 28% at age 59, 51% at age 69,
and 74% at age 79, but other studies report lower odds.
This mutation has only been observed in European,
Ashkenazi Jewish, and Arab-Berber populations.
LRRK2 mutations linked to PD
G2385R
The G2019S mutation
increases kinase
activity in HEK-293T
cells.
LRRK2 mutations linked to PD
G2385R
Among Asian populations, carriers of the G2385R
mutation have a 3 fold increased risk for PD.
The mutation is located in the WD40 domain of
the protein, and has an unknown effect on its
activity.
PD Risk Loci
SNP: i4000415
Gene name: GBA
Risk Allele: C
Odds ratio: 3.51 (European)
P-value: 1.4E-14
This SNP lies in the GBA gene, which encodes glucocerebrosidase.
Deficiency of this protein results in Gaucher’s disease, which leads to the
accumulation of glucocerebrosides (fatty acids).
The mechanism by which mutant form of the protein leads to PD is unknown,
but is thought to involve aberrant handling and clearance of α-synuclein.
Particularly relevant to Ashkenazi Jewish individuals, not observed in Asian
Populations.
PD Risk Loci
SNP: rs356220
Gene name: SNCA
Risk allele: T
Odds ratio: 1.38
P-value: 3E-11
This SNP lies near the gene encoding
α-synuclein. It likely contributes to PD risk via
increased expression of the protein.
PD Risk Loci
SNP: rs393152
Gene name: MAPT (Microtubule associated protein tau)
Risk allele: G
Odds ratio: 1.30 (European)
p-value: 2E-16
The tau protein has been implicated in a number of neurodegenerative
diseases, termed tauopathies, including Alzheimer’s. Tau has been
detected in Lewy bodies, suggesting a role in PD pathogenesis.
This association was not replicated in a large study of Japanese
individuals.
PD Risk Loci
SNP: rs947211
Gene name: SLC41A1/RAB7L1
Risk allele: G
Odds ratio: 1.30 (European)
P-value: 2E-12
SNP: rs823156
Gene name: SLC41A1
Risk allele: A
Odds ratio: 1.2100 (Asian)
P-value: 1E-7
SLC41A1 is a magnesium (Mg2+) transporter. Mg2+ deficiency is thought to be an environmental
risk factor for PD.
RAB7L1 is a small GTP-binding protein that plays an important role in regulation of exo- and
endocytotic pathways.
PD Risk Loci
SNP: rs4698412
Gene name: BST1
Risk allele: A
Odds ratio: 1.1400
P-value: 0.000002
This SNP is located near the BST1 gene, the product of which
catalyzes formation of cyclic ADP-ribose, involved in calcium
homeostasis.
Sensitivity to disruption of calcium homeostasis has recently been
proposed to be a cause of selective dopaminergic neuron
vulnerability.
PD Risk Loci
SNP: rs11248060
Gene name: DGKQ
Risk allele: T
Odds ratio: 1.21 (European)
P-value: 3E-12
This SNP is located within the DGKQ gene, which encodes
a protein called diacylglycerol kinase theta.
Its possible role in PD pathogenesis is uncharacterized.
PD Risk Loci
SNP: rs2390669
Gene name: STK39
Risk allele: C
Odds ratio: 1.19 (European)
P-value: 1.37E-9
This SNP is located within the STK39 gene, which
encodes a protein kinase that is thought to be
involved in the cellular response to oxidative stress.
Risk reduction
One of the early warning signs of PD is a reduction in the
levels of glutathione (GSH), the major endogenous antioxidant.
Dietary supplements of anti-oxidants may reduce risk for
PD. Magnesium supplements may also be protective.
Regular exercise has also been found to be associated with
reduced incidence of the disease.
Limiting exposure to pesticides would also decrease risk.
Thanks for listening!
Questions?