Parkinson's as Autophagy Failure

Autophagy is important in determining life span, probably because of its role in clearing out damaged mitochondria (a process known as mitophagy) before they can cause other forms of harm. Here is evidence for that view in the form of a link between Parkinson's disease and autophagy: "Mutations that cause Parkinson's disease prevent cells from destroying defective mitochondria ... Defects in the ubiquitin ligase Parkin are linked to early-onset cases of this neurodegenerative disorder. The wild-type protein promotes the removal of impaired mitochondria by a specialized version of the autophagy pathway called mitophagy, delivering mitochondria to the lysosomes for degradation. Mitochondria are often dysfunctional in Parkinson's disease ... cells expressing mutant forms of Parkin failed to clear their mitochondria after the organelles were damaged. Different mutations blocked mitophagy at distinct steps: mitochondria accumulated in the perinuclear region of cells expressing Parkin lacking its ubiquitin ligase activity, for example. The researchers found that ubiquitination of defective mitochondria by Parkin normally recruits the autophagy proteins HDAC6 and p62 to clear these mitochondrial aggregates. ... The clearance of defective mitochondria is therefore similar to the removal of damaged proteins, another autophagic process that goes wrong in Parkinson's disease resulting in the accumulation of toxic protein aggregates. Both pathways rely on microtubules, HDAC6, and p62, [providing] a common link between the two main features of the neurodegenerative disorder."



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