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 of "Genetic Basis Of Parkinson Disease"
Basal Ganglia<br />a large group of nuclei at the base of the cerebral cortex that controls movement, coordination & affects voluntary movement <br />Including :<br /> - caudate nucleus<br /> - putamen<br /> - globus pallidus<br /> - subthalamic nucleus<br /> - substantia nigra<br />
Parkinson Disease?<br />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<br />Symptom 60-80 % cell impaired<br />
Levodopa + Carbidopa<br />Dopamine production in the brain<br /> Side effects<br /> Carbidopa : inhibits dopa decarboxylase outside the BBB<br />
Surgical treatment<br />Pallidal surgery<br />Thalamic surgery<br />Subthalamic surgery <br />Transplantation surgery <br />
Genetic basis of PD<br />Most PD cases are sporadic<br />5–10% of PD patients carry a mutation causing monogenic form of the disorder<br />These genes also play a role in the sporadic form of the disease<br />Different genes influence: <br />Inheritance pattern<br />Phenotype<br />Age of onset<br />
PARK2 <br />Parkin was the first gene identified for AR form of PD<br />Very common cause of parkinsonism<br />Localize at synapse, function as ubiquitinligase at ubiquitination protein degradation pathway<br />Severe and selective degeneration in substantianigra pars compacta without Lewy bodies<br />Mutations: missense, nonsense, rearrangement<br />Onset before 40 years, slow progression, dystonia occurring early and frequently<br />Unusual feature: focal dystonia, early postural instability, autonomic failure<br />
PARK8 (LRRK2)<br />PARK8 encodes multidomain protein, leucine-rich repeat kinase 2 (LRRK2); <br />mutations cause autosomal dominant PD <br />α-synuclein-type neuropathology<br />Mutations account for 3-7% of familial PD cases, 0.5-3% of sporadic cases<br />c.6055G > A; p.G2019S is the most frequent of several amino acid substitutions in PARK8 gene<br />Prevalence vary with ethnicity of PD patients: <br />North American and Northern European white population (1-2%) <br />Portuguese (6%)<br />Ashkenazi Jewish (18.3%) <br />North African Arab populations (39%)<br />Rare in Korean population<br />
Common intersecting pathway in PD<br />Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94. Review.<br />
Genetic susceptibility in sporadic PD<br />90% of PD: complex interaction of genetics and environment<br />Environmental risk factors: association between pesticide use, use of well water, rural living, and agricultural employment (conflicting results)<br />Specific polymorphic variants have been validated as genetic susceptibility factors<br />The Rep1, a mixed nucleotide repeat in the promoter region of SNCA, has been confirmed as a risk factor.<br />Two variants in the LRRK2 gene, G2385R and R1628P, confer susceptibility to PD in Asian populations. <br />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.<br />
Genetic modifiers<br />Krüger R. LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary.<br />BMC Med. 2008 Nov 5;6:33.<br />
Conclusion<br />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)<br />Specific polymorphic variants have been validated as genetic susceptibility factors and protective factors (Xiromerisiou G et al, 2010)<br />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)<br />
References<br />Krüger R. LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary. BMC Med. 2008 Nov 5;6:33.<br />Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94. Review.<br />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.<br />