Mechanisms of neurodegeneration in Parkinson's disease: keep neurons in the PINK1. (July 2020)

• Record Type: Journal Article
• Authors: Brunelli, Francesco; Valente, Enza Maria; Arena, Giuseppe
• Is Part Of: Mechanisms of ageing and development. Volume 189(2020)
• Publication Date: 2020-07
• Subjects: Parkinson's disease -- PINK1 -- Mitochondrial function -- Induced pluripotent stem cells (iPSC) -- Neurodegeneration; Aging -- Periodicals; Developmental biology -- Periodicals; Aging -- Periodicals; Developmental Biology -- Periodicals; Vieillissement -- Périodiques; Biologie du développement -- Périodiques; Aging; Developmental biology; Periodicals; 612.67
• DOI: 10.1016/j.mad.2020.111277
• Languages: English
• ISSNs: 0047-6374

Abstract

Highlights: Most PINK1 prosurvival functions have been described in immortalized cells and fibroblasts from PD patients. Some of the findings observed in non-neuronal models have not been reproduced in neurons. Patient-specific iPSC-derived dopaminergic neurons represent a more trustworthy model to study PD pathophysiology. Abstract: Extensive studies on PINK1, whose mutations are a confirmed cause of Parkinson's disease (PD), have been conducted in animal models or immortalized cell lines. These include initial ground-breaking discoveries on mitophagy, which demonstrated that PINK1 recruits Parkin on depolarized mitochondria, initiating a signalling cascade eventually resulting in their autophagic degradation. Not all features of this complex molecular pathway have been reproduced in mammalian or human neurons, undermining the hypothesis proposing mitophagy as the most relevant biochemical link between PINK1 deficiency and PD pathogenesis. Experiments in murine primary neurons examined another possible neuroprotective function of PINK1, namely its involvement in mitochondrial motility along axons and dendrites. PINK1 interacts with Miro, a component of the motor/adaptor complex binding mitochondria to microtubules and allowing their movement to and from cellular processes. Distinct subcellular pools of PINK1, cytosolic and mitochondrial, appear to regulate anterograde and retrograde transport, respectively. Technological advancements today allow researchers to de-differentiate fibroblasts into induced pluripotent stem cells and re-differentiate them into dopaminergic neurons. Few studies based on this technique address possible neuroprotective effects of PINK1, including mitophagy and mitochondrial homeostasis, but underline the need for a broader characterization of its function in neurons.