Mechanisms of neurodegeneration in Parkinson's disease: keep neurons in the PINK1

Francesco Brunelli, Enza Maria Valente, Giuseppe Arena

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number111277
JournalMechanisms of Ageing and Development
Volume189
DOIs
Publication statusPublished - Jul 2020

Keywords

  • Induced pluripotent stem cells (iPSC)
  • Mitochondrial function
  • Neurodegeneration
  • Parkinson's disease
  • PINK1

ASJC Scopus subject areas

  • Ageing
  • Developmental Biology

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