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.

Keywords: Familial Parkinson's disease; Parkin; ubiquitin–proteasome system; autophagy; mitochondria

Figure 1.

Mutations found in parkin.

Figure 2.

Parkin acts as an E3 ligase in the ubiquitin–proteasome system. Ubiquitin is covalently attached by substrate proteins (target proteins) via three‐step process. First, E1 (activating enzyme) activates the ubiquitin in an ATP‐dependent manner. Second, activated ubiquitin is transferred to E2 (conjugating enzyme). Third, E3 ligase (ubiquitin protein ligase) recognises the target proteins and mediates the transfer of ubiquitin from E2 via an isopeptide bond to specific internal Lys residues of target proteins. Finally, a polyubiquitin chain is formed by repeating these steps. Ubiquitin chains linked via Lys 48 of ubiquitin are recognised and degraded by proteasomes. However, several reports suggested that parkin associates with non‐Lys 48 linked ubiquitin chains, including monoubiquitin, Lys 63, and Lys 27 linked ubiquitin chains. Therefore, parkin participates in the ubiquitin–proteasome degradation system as well as autophagy, signal transduction, membrane trafficking, etc.

Figure 3.

Parkin/PINK1 pathway regulates the selective elimination of damaged mitochondria by autophagy (mitophagy). Treatment with CCCP reduced mitochondrial transmembrane potential and leads to mitochondrial fragmentation. PINK1 accumulates in the mitochondria with low membrane potential and recruits parkin from the cytoplasm to depolarised mitochondria. The kinase activity of PINK1 is prerequisite for the mitochondrial translocation of parkin. In damaged mitochondria, parkin exerts its E3 activity and ubiquitylates mitochondrial proteins. Geisler et al. described parkin mediates K63 linked poly ubiquitylation of itself and K27‐linked polyubiquitylation of VDAC1. Finally, p62, which is the ubiquitin‐autophagy adaptor protein, is recruited to the damaged mitochondria and is essential for parkin‐dependent mitophagy. The interaction between LC3 and PINK1 also contribute to mitophagy.

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Hatano, Taku, and Hattori, Nobutaka(May 2011) Parkinson Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006026.pub2]