Autosomal Recessive Parkinson' Disease Related to Parkin ( PARK2 ) Mutations

Abstract

Abstract Parkinson 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 20 genetic loci and causative genes have been identified so far, and many studies have examined their effects on monogenic and sporadic forms of PD. The encoded proteins participate in several cellular functions, including membrane trafficking, and protein and lipid degradation. Mutations in parkin ( PARK2 ) are the most common cause of autosomal recessive early‐onset PD. Parkin functions as an E3 ubiquitin ligase, which monoubiquitinates and polyubiquitinates target proteins. Consequently, parkin participates in multiple cellular processes, such as protein degradation, mitochondrial function, membrane trafficking, lipid metabolism and endoplasmic reticulum stress. Parkin can interact with other familial PD‐associated proteins, possibly within a common pathway that leads to nigral degeneration. There is evidence of a PINK1/parkin pathway involving autophagic mitochondrial degradation. Recent investigations involving imaging and blood biomarkers revealed several alterations associated with parkin dysfunction. Key Concepts Parkinson disease ( PD ) is the second most frequent neurodegenerative disease after Alzheimer disease. Approximately 5% of PD patients have a clear familial aetiology, exhibiting a classical recessive or dominant Mendelian mode of inheritance. Parkin ( PARK2 ) is the most prevalent gene associated with early‐onset Parkinsonism and is associated with approximately 50% of recessive familial patients with an onset under 45 years of age. Abnormal imaging and blood biomarkers are associated with parkin dysfunction. Parkin functions as an E3 ubiquitin ligase, which participates in the ubiquitin–proteasome ( Ub‐Pr ) system. Collaboration between parkin and PINK1 promotes the autophagic degradation of damaged mitochondria. Parkin can participate in several pathways that lead to dopaminergic neuronal degeneration, such as the Ub‐Pr system, autophagic protein degradation, the mitochondrial quality control system, the membrane trafficking system and lipid metabolism.