Genetic Basis Of Parkinson Disease

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Literature review

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  • Figure 1. Common intersecting pathways underlying PD pathogenesis. Both environmental factors and mutations in familial PD-linked genes encoding a-synuclein, parkin, DJ-1, PINK1 and LRRK2 are associated with PD pathogenesis. These pathogenic mutations and environmental factors are known to cause disease due to mitochondrial dysfunction, oxidative damage, abnormal protein aggregation and protein phosphorylation compromising key roles of dopaminergicneuronal function and survival. Environmental factors similar to pesticides and toxins directly induce both oxidative damage and mitochondrial dysfunctions.a-Synuclein undergoes aggregation either due to pathogenic mutations or catechol oxidation which in turn compromise ubiquitinproteasome function (UPS), induce ER stress and cause mitochondrial dysfunction. Mitochondrial dysfunction and oxidative damage lead to deficits in ATP which may compromise UPS function promoting abnormal protein aggregation. b-Synuclein is known to prevent a-synuclein aggregation through activation of Akt signaling. Parkin, an ubiquitin E3 ligase, promotes proteasomal degradation, increases mitochondrial biogenesis by activating mitochondrial transcription factor A (TFAM) and block PINK1-induced mitochondrial dysfunction, while pathogenic mutations, oxidative and nitrosative damage severely compromise its protective function. DJ-1 protects against oxidative stress, functions as a chaperone to block a-synuclein aggregation and protects against mitochondrial dysfunction. PINK1 seems to protect against mitochondrial dysfunction which is compromised due to pathogenic mutations, although the precise function of PINK1 in mitochondria still needs to be determined. LRRK2 seems to play a role in synaptic vesicle functions, neurite outgrowth, etc. Pathogenic mutations in LRRK2 cause abnormal protein phosphorylation which induce mitochondria-dependent cell death. In addition, a neuroprotective role of PGC-1a in preventing oxidative damage and mitochondrial dysfunction is suggested, whereas a pathogenic role of PI3kinase-Akt (phosphatidylinositol 3-kinase/Akt) and Nrf2/ARE signaling is implicated in PD pathogenesis. Familial PD-linked genes namely parkin, DJ-1 and PINK1 activate PI3 kinase-Aktsignaling, while activation of Nrf2/ARE pathway prevents against oxidative damage and mitochondrial dysfunction promoting cell survival. Both PI3 kinase-Akt and Nrf2/ARE signaling could be explored as potential targets of therapeutic intervention in dopaminergic neuronal demise. Green arrows indicate promoting or activating effects while red lines with blunt ends indicate inhibitory effects.

Transcript

  • 1. PARKINSON DISEASE
    Literature Review by:
    Galuh DN Astuti, MD
    RahajengTunjungputri, MD
    Magister of Biomedical Science/ Genetic Counseling
    Faculty of MedicineDiponegoro University, 2010
  • 2. Parkinsonism
    Parkinson disease
    Parkinsonism in other neurodegenerative disorders
    - Pick disease
    - Progressive supranuclear palsy
    - Multiple System atrophies
    - Alzheimer disease
    - Huntington disease (rigid variant)
    Secondary Parkinsonism
    drug-induced, infection, toxin, tumors
  • 3. Parkinson Disease ?
    a chronic progressive neurodegenerativemovement disorder characterized by aprofound & selective loss of nigrostriataldopaminergic neurons with accumulation of Lewy bodies (protein aggregate)
    2nd most common neurodegenerative disorder after Alzheimer disease
    Prevalence : 0.5 - 1 %(65 - 69 y.o)
    1 - 3 %(> 80 y.o)
    men > women
    all races and ethnic groups are affected
  • 4. Clinical manifestation :TRAP
    Tremor at rest
    Rigidity
    Akinesia (or bradykinesia)
    Posturalinstability
    Autonomic dysfunction
    Neuropsychiatric disorder
  • 5. ETIOLOGY
    Unknown
    Interaction between environmental and genetic factor
  • 6. Risk factors
    Increasing age
    Family history
    Male gender
    Caucasian
    Personality
    Environmental risk factors
  • 7. Basal Ganglia
    a large group of nuclei at the base of the cerebral cortex that controls movement, coordination & affects voluntary movement
    Including :
    - caudate nucleus
    - putamen
    - globus pallidus
    - subthalamic nucleus
    - substantia nigra
  • 8.
  • 9. Parkinson Disease?
    breakdown the connection between neurons in substantia nigra and putamen portion of striatum  loss of dopaminergic neurons  decrease in neurotransmission  dysfunction of globus pallidus interna and subthalamic  difficulty of motor control
    Symptom  60-80 % cell impaired
  • 10.
  • 11. DIAGNOSIS
    History taking
    Physical Examination
    No laboratory tests or imaging studies to confirm the diagnos
    Antiparkinsonian medication?
    Imaging test:
    - MRI
    - CT scan
    - PET
    - SPECT
    Dopamine transporter imaging
  • 12. Treatment
    Indication:
    • when the patient is sufficiently botheredby symptoms to desire treatment
    • 13. when the diseaseis producing disability
    Non Pharmalogical
    support and education
    exercise : stretching, strengthening, cardiovascular fitness & balance training
    Pharmacotherapy
    - Levodopa
    - Anticholinergics
    - Amantadine
    - MAO-B inhibitors
    - Dopamine agonists
    - COMT inhibitor
  • 14. Levodopa
    dopa decarboxylase
    Levodopa dopamine
    Complication :
    - Wearing off
    - Dose failures
    - ON-OFF
    - Dyskinesias & dystonia
  • 15. Levodopa + Carbidopa
    Dopamine production in the brain
    Side effects
    Carbidopa : inhibits dopa decarboxylase outside the BBB
  • 16. Surgical treatment
    Pallidal surgery
    Thalamic surgery
    Subthalamic surgery
    Transplantation surgery
  • 17. Genetic basis of PD
    Most PD cases are sporadic
    5–10% of PD patients carry a mutation causing monogenic form of the disorder
    These genes also play a role in the sporadic form of the disease
    Different genes influence:
    Inheritance pattern
    Phenotype
    Age of onset
  • 18. Role of genes in PD
  • 19. Monogenic forms of PD
    Xiromerisiou G, Dardiotis E, Tsimourtou V, Kountra PM, Paterakis KN, Kapsalaki EZ, Fountas KN, Hadjigeorgiou GM. Genetic basis of Parkinson disease. Neurosurg Focus. 2010 Jan;28(1):E7.
  • 20. PARK1, PARK4
  • 21. PARK2
    Parkin was the first gene identified for AR form of PD
    Very common cause of parkinsonism
    Localize at synapse, function as ubiquitinligase at ubiquitination protein degradation pathway
    Severe and selective degeneration in substantianigra pars compacta without Lewy bodies
    Mutations: missense, nonsense, rearrangement
    Onset before 40 years, slow progression, dystonia occurring early and frequently
    Unusual feature: focal dystonia, early postural instability, autonomic failure
  • 22. PARK8 (LRRK2)
    PARK8 encodes multidomain protein, leucine-rich repeat kinase 2 (LRRK2);
    mutations cause autosomal dominant PD
    α-synuclein-type neuropathology
    Mutations account for 3-7% of familial PD cases, 0.5-3% of sporadic cases
    c.6055G > A; p.G2019S is the most frequent of several amino acid substitutions in PARK8 gene
    Prevalence vary with ethnicity of PD patients:
    North American and Northern European white population (1-2%)
    Portuguese (6%)
    Ashkenazi Jewish (18.3%)
    North African Arab populations (39%)
    Rare in Korean population
  • 23. Common intersecting pathway in PD
    Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94. Review.
  • 24. Genetic susceptibility in sporadic PD
    90% of PD: complex interaction of genetics and environment
    Environmental risk factors: association between pesticide use, use of well water, rural living, and agricultural employment (conflicting results)
    Specific polymorphic variants have been validated as genetic susceptibility factors
    The Rep1, a mixed nucleotide repeat in the promoter region of SNCA, has been confirmed as a risk factor.
    Two variants in the LRRK2 gene, G2385R and R1628P, confer susceptibility to PD in Asian populations.
    Polymorphisms in genes identified in familial PD may exert a disease-modulating effect that, interacting with other genetic or environmental susceptibility factors, may drive the accumulated risk over a critical threshold to cause neurodegeneration.
  • 25. Genetic modifiers
    Krüger R. LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary.
    BMC Med. 2008 Nov 5;6:33.
  • 26. Conclusion
    The value of screening for mutations in asymptomatic family members of LRRK2-mutation carriers are still questionable because until now no neuroprotective therapy has been implemented and symptomatic treatment is performed regardless of the presence or absence of mutations in known genes (Kruger, 2008)
    Specific polymorphic variants have been validated as genetic susceptibility factors and protective factors (Xiromerisiou G et al, 2010)
    Knowledge of genetic basis of PD will discover key facts of the pathogenesis and lead to new targeted therapeutic strategies in the future (Xiromerisiou G et al, 2010)
  • 27. References
    Krüger R. LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary. BMC Med. 2008 Nov 5;6:33.
    Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94. Review.
    Xiromerisiou G, Dardiotis E, Tsimourtou V, Kountra PM, Paterakis KN, Kapsalaki EZ, Fountas KN, Hadjigeorgiou GM. Genetic basis of Parkinson disease. Neurosurg Focus. 2010 Jan;28(1):E7.