Parkinson Disease

Abstract

Parkinson's disease (PD) is a common movement disorder caused by loss of dopaminergic neuronal cells. The molecular mechanisms underlying neuronal degeneration in PD remain unknown; however, it is clear that genetic factors contribute to its pathogenesis. Over 15 loci and 11 causative genes have been identified so far, and many studies examine their effects on monogenic and sporadic forms of PD. Parkin mutations are the most common cause of autosomal recessive early onset PD. Parkin functions as an E3 ubiquitin ligase, which monoubiquitinates and polyubiquitinates the target proteins. Consequently, parkin participates in multiple cellular processes, such as protein degradation, mitochondrial function, endoplasmic reticulum stress, and membrane trafficking. Parkin could interact with other familial PD‐associated proteins and may share a common pathway that leads to nigral degeneration. There is evidence of a PINK1/Parkin pathway involving autophagic mitochondrial degradation. We review how parkin is associated with the pathogenesis of PD. Key Concepts: Parkinson's disease is the second most frequent neurodegenerative disease after Alzheimer's disease. Approximately 5% of patients with Parkinson's disease have a clear familial aetiology, exhibiting a classical recessive or dominant Mendelian mode of inheritance. Parkin is the most prevalent gene associated with early onset Parkinsonism, accounting for around 50% of recessive familial patients with an onset under 45 years of age. Parkin functions as an E3 ubiquitin ligase, which participates in the ubiquitin–proteasome (Ub–Pr) system. The collaboration between parkin and PINK1 promotes the autophagic degradation of damaged mitochondria. Parkin could participate in several pathways which lead to dopaminergic neuronal degeneration, such as the Ub–Pr system, autophagic protein degradation, the mitochondrial quality control system, the membrane trafficking system, and endoplasmic reticulum stress.

Metabolomics‐based identification of metabolic alterations in PARK2

“…Moreover, selective dopaminergic neuronal degeneration in the substantia nigra pars compacta without Lewy body (LB) formation is considered a characteristic pathological finding of PARK2, although LB‐positive cases have also been reported . Parkin functions as an E3 ubiquitin ligase in the ubiquitin–proteasome system (UPS), and monoubiquitinates and polyubiquitinates target proteins . UPS is a protein degradation system, and LBs are strongly stained for anti‐ubiquitin antibodies.…”