Medical doctor, lecturer of parasitology, PhD student of infectious diseases
Radboud University Nijmegen, The Netherlands - Faculty of Medicine Diponegoro University
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
ETIOLOGY Unknown Interaction between environmental and genetic factor
Risk factors Increasing age Family history Male gender Caucasian Personality Environmental risk factors
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
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
Levodopa + Carbidopa Dopamine production in the brain Side effects Carbidopa : inhibits dopa decarboxylase outside the BBB
Surgical treatment Pallidal surgery Thalamic surgery Subthalamic surgery Transplantation surgery
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
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
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
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.
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.
Genetic modifiers Krüger R. LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary. BMC Med. 2008 Nov 5;6:33.
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)
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.