Parkinson's Disease

 Parkinson’s disease is a progressive neurodegenerative disorder characterised by slowness of initiation of, and a progressive reduction in, the speed and amplitude of sequential movements with muscular rigidity and a coarse slow pill rolling rest tremor. The pathological signature most frequently associated with this clinical picture is severe loss of pigmented neurons in the ventrolateral tier of the pars compacta of the substantia nigra with the presence of distinctive α synuclein immunoreactive inclusions in surviving nigral neurons (Lewy bodies).



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PD Genes and Molecular Pathogenesis

 Sophisticated genetic analysis has revealed several PD-associated genes including those encoding α-synuclein, parkin, PINK1, DJ-1and LRRK2.


 α-Synuclein: Even though the physiological function of α-synuclein is still unclear, numerous studies indicate its association with membranes, synaptic vesicle recycling, dopamine neurotransmission, and lipid interactions. This protein is the major structural component of Lewy bodies, which are the pathological hallmark of PD. In sporadic PD, reactive oxygen species (ROS), reactive nitrogen species (RNS), and aging play a role in the aggregation of α-synuclein. ROS/RNS production, disruption of macroautophagy, mitochondrial dysfunction, and proteasome inhibition can also be triggered by mutant or aggregated α-synuclein.

 LRRK2: LRRK2 consists of diverse domains, including a leucine-rich repeat, a Roc GTPase domain, a COR (C-terminal of Ras) domain, a kinase domain, and a WD40-repeat. LRRK2 is localized in the cytoplasm and is associated with membranous structures including mitochondria, the ER, and synaptic vesicles. Familial mutants of LRRK2 result in a gain of function and neuronal toxicity that is kinase dependent. Functional studies implicate LRRK2 in neurite outgrowth, the endocytosis of synaptic vesicles and mitochondrial function. Disease-causing mutations in human LRRK2 consistently cause α-synuclein pathology.


 PINK1: PINK1 is a mitochondrial kinase that acts upstream of parkin in the PD pathogenesis cascade. The mitochondrial chaperone, TRAP1, and the serine protease, HtrA2, are putative PINK1 substrates that play important roles in regulating mitochondrial function and mitochondrial-dependent cell death pathways. PINK1 may also physiologically regulate Ca2+ efflux from the mitochondria via NCK.

 DJ-1: DJ-1 is a molecular chaperone with multiple functions. Disease-causing mutations in DJ-1 may lead to a loss of function. DJ-1 regulates ROS levels by acting as an atypical peroxiredoxin-like peroxidase and also modulates RNA metabolism and gene transcription. DJ-1 is also involved in a Parkin-PINK1-DJ-1 (PPD) complex that promotes the degradation of unfolded proteins.

 Parkin: Mutations in the parkin gene and posttranslational modifications to the protein block parkin’s ability to function as an E3 ubiquitin ligase. This leads to the accumulation of its substrates which are somehow involved in mitochondrial dysfunction and neuronal toxicity. Parkin acts downstream of PINK1 in genetic models and appears to play a role in the clearance of mitochondria by autophagy (mitophagy).