Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease

Abstract

The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.

The Mechanism and Function of Glia in Parkinson's Disease

“…Although α-syn induces the response of various cells in CNS, recent studies also suggest that microglia and astrocytes play a minor role in the development of PD (Vizziello et al, 2021), the neurons themselves are more related to PD. The microglia and astrocytes play the role in regulating the neuroinflammatory response induced by α-syn.…”

“…The progression in oligodendrocytes has been detected in multiple system atrophy (MSA), a rare and atypical PD (Tu et al, 2021). An analysis sequence of about 17,000 nuclei from matched SN samples found that dopaminergic neuronspecific gene expression makes up the crucial genetic risk for PD, such as protein folding and ubiquitination pathways, mitochondrial functioning, and a distinct cell type associated with PD and oligodendrocyte-specific gene expression (Vizziello et al, 2021).…”

Precision Medicine in Parkinson’s Disease: From Genetic Risk Signals to Personalized Therapy

“…The atypical features are dystonia, sleep benefit, and hyperreflexia [ 47 ]. Similar to PRKN, PINK1 contributes to the maintenance of mitochondrial homeostasis and regulates UPS function [ 21 , 243 ]. PINK1 mutations induce a complete loss of kinase activity, mitochondrial dysfunction, oxidative stress, impaired cellular metabolism, abnormal mitophagy, and altered proteostasis [ 21 , 47 ].…”

Defective PTEN-induced kinase 1/Parkin mediated mitophagy and neurodegenerative diseases

“…Interestingly enough, the great majority of these mutations appear to affect the nervous system. For example, mutations in PINK1 and Parkin are associated with early-onset forms of Parkinson’s Disease (PD) ( Borsche et al, 2021 ; Vizziello et al, 2021 ) while mutations in MFN2 are associated with axonal forms of Charcot-Marie-Tooth disease 2 (CMT2) and hereditary motor and sensory neuropathies (HMSN) ( Zaman and Shutt, 2022 ). Finally, mutations in OPTN have been linked to primary forms of glaucoma ( Sears et al, 2019 ) as well as amyotrophic lateral sclerosis (ALS) ( Benson et al, 2021 ).…”