*2.2. Parkinson's Disease*

PARKIN, or Parkinson Protein 2 (PARK2), is a RBR-type E3 ubiquitin ligase mutated in autosomal recessive juvenile parkinsonism [51], a form of familial Parkinson's disease, defined by an onset before 40 years of age and characterized by slow movement and tremor (Table 1). *PARK2* is also mutated in other neurological diseases such as retropulsion, dystonia, hyperreflexia, and sensory axonal neuropathy [91] causing olfactory impairment [92]. In these di fferent pathologies, loss of PARK2 function causes death of selective neuron populations, such as the dopaminergic neurons [93]. Deletion of *Parkin* in mice leads to motor and cognitive deficits [94] caused by catecholaminergic neuronal death and the subsequent loss of norepinephrine in some regions of the brain [95]. The *Parkin* knockout mice also show enhanced hepatocyte proliferation, macroscopic hepatic tumors in aged mice, higher sensitivity to myocardial infarction, and a strong inflammatory phenotype [96].

PARKIN maintains mitochondrial health through mitochondrial quality control and generation of mitochondrial-derived vesicles, followed by whole-organellar degradation, a process called mitophagy [97]. Mitophagy is vital for the removal of damaged mitochondria and toxic mitochondrial proteins, protecting neuronal cells from apoptosis [49]. Dysregulation of these processes plays a key role in Parkinson's disease [50]. PARKIN was shown to mediate both polyubiquitination and monoubiquitination depending on the protein context [47]. This dual activity of PARKIN di fferentially a ffects function of its substrates such as voltage-dependent anion-selective channel 1 (VDAC1), which transports ions and small molecules at the mitochondrial outer membrane. Defect in VDAC1 polyubiquitination hinders PARKIN-mediated mitophagy, whereas dysregulation of VDAC1 monoubiquitination induces apoptosis. This suggests that the dual regulation of mitophagy and apoptosis by Parkin via VDAC1 poly- and monoubiquitination is critical in protecting cells from the pathogenesis of Parkinson's disease [48] (Figure 1B). PARKIN also mediates the multi-monoubiquitination of heat shock protein 70 (HSP70) and heat shock cognate 70 (HSC70), leading to their association to insoluble substrates, consistent with a degradation-independent role for this type of ubiquitin modification [98]. These data strongly implicate PARKIN-mediated monoubiquitination in the development of Parkinson's disease.
