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.
Highlights
Parkinson’s disease (PD) is the second most common degenerative neurological disorder after Alzheimer’s disease
The aim of this paper is to explore the role of PINK-1 in the pathogenesis of PD
An important piece of evidence is that “post-natal conditional Parkin k.o.” mice results in loss of nigral DA neurons, suggesting a possible compensatory mechanism to be responsible for neuronal integrity preservation in germline k.o. [131]. It is still not clear how this mechanism could work, but Parkin-independent mitophagy pathways may play a role in compensating Parkin deficiency; anyway, this evidence invariably underlines an inconsistency between mice and humans, since PINK1/Parkin loss leads to marked, early-onset neurodegeneration in human
Summary
Parkinson’s disease (PD) is the second most common degenerative neurological disorder after Alzheimer’s disease. Molecular mechanisms underlying the degeneration of this specific neuronal population are still largely unclear, but it is known that these cells have a large axonal architecture and a so-called pacemaking activity, which puts them under an extreme bioenergetic demand for the propagation of action potentials, maintenance of membrane potential and synaptic transmission [1,2] These distinctive features account for the essential role of mitochondrial dysfunction in PD pathogenesis, as demonstrated by the finding that exposure to environmental mitochondrial toxins leads to PD-like pathology [3]. Evidence of this is that PINK1 and Parkin, both involved in mitochondrial dynamics and quality control, are the main cause of autosomal recessive (AR) early-onset PD [4,5,6]. We will focus on the potential novel therapeutic approaches targeting the mitophagy pathway
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