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 Parkinson’s Disease Pathway

Parkinson’s/Parkinson disease (PD) is a chronic and progressive neurodegenerative disorder characterized by muscle rigidity, tremor and bradykinesia. The central aspect of PD involves dysmetabolism of specific proteins resulting in aggregation, aborted protein degradation and/or formation of Lewy bodies. PD involves the progressive loss of dopamine-containing neurons from the substantia nigra. This loss is frequently associated with the presence of neuronal cytoplasmic inclusions, Lewy bodies and/or Pael-R associated ER stress. Most cases of PD are (primary parkinsonism) late-onset, sporadic and idiopathic (of unknown cause). However early- and late-onset genetically-linked forms of PD (familial PD) have been identified and associated with several gene mutations including the α-synuclein (SNCA), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), ubiquitin-protein ligase (Parkin), DJ-1 (PARK-1), leucine-rich repeat kinase 2 (dardarin) (LRRK2), and PTEN induced putative kinase 1 (PINK1) genes.

Lewy bodies are proteinaceous cytoplasmic inclusions that promote neural cell death. Factors that promote the formation of Lewy bodies within nigra dopaminergic neurons promote PD. Lewy bodies result from dysfunctions affecting the ubiquination and proteosome-mediated degradation of specific proteins. Alpha synculein, synphilin-1 and parkin are component of Lewy bodies. Mutation in α-synuclein can lead to mis-folding, aggregation and resistance to protein degradation. Parkin is a multi-faceted ubiquitin-protein ligase whose substrates include CDCrel-1, synphilin-1 (an α-synuclein-interacting protein), o-glycosylated forms of α-synuclein (αSp22) and Parkin associated endothelin-receptor like receptor (Pael-R). Parkin promotes the survival of dopaminergic neurons by facilitating the degradation of α-synuclein, synphilin-1 and other proteins. Under some conditions, Parkin can enhance the formation of Lewy-body like inclusions by protesomal-independent ubiquination of Lewy body proteins; parkin ubiquitinates synphilin-1 via nonclassical K63-linked ubiquitin chains. Pael-R induces endoplasmic reticulum (ER) stress and consequent apoptotic dopaminergic neuron death. Parkin together with HRD1 protects dopaminergic cells from ER stress induced death by facilitating Pael-R proteosome-mediated degradation.