Editors' ChoiceNeurology and Autophagy

Slippery Cargo Ends in Death

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Science Translational Medicine  16 Jun 2010:
Vol. 2, Issue 36, pp. 36ec96
DOI: 10.1126/scitranslmed.3001356

A genetic neurodegenerative disorder that strikes relatively early in life, Huntington's disease (HD) follows an inexorable course that ultimately leads to death for all afflicted individuals. HD arises from an alteration in the huntingtin protein that causes the protein to accumulate and form toxic aggregates in nerve cells. The normal fuction of huntingtin remains somewhat obscure, although recent evidence suggests that it may be necessary for proper performance of the cell's autophagic system. Autophagy is a quality-control process for the cell that clears abnormal or damaged cellular components. A recent study by Martinez-Vicente and colleagues shows that cells from HD mice and patients may fail to properly trap cytosolic cargo in autophagic vacuoles for elimination.

The authors characterized multiple cell types from two mouse models of HD and lymphoblasts from the bone marrow of HD patients using a variety of biochemical, functional, and morphological assays. They found impairments in protein degradation suggestive of dysfunctional macroautophagy—a process in which whole regions of the cytosol are delivered to lysosomes for degradation. This aberration was observed in embryonic fibroblasts and neurons from the mouse models and in the patient-derived lymphoblasts. Neither lysosomal pH nor proteolytic efficiency was altered, observations that argue against a primary defect in mature lysosomes; in fact, some measures even suggested a paradoxical increase in macroautophagic flux. Electron microscopic examination of neurons from the HD mice and patient lymphoblasts revealed an increase in the number and size of autophagic vacuoles as compared with that of normal cells, but these vacuoles appeared to be empty; that is, they lacked organelle cargo, such as discarded mitochondrial or cytosolic proteins. In contrast, the authors observed an increase in the cellular content of cytosolic organelles, such as lipid droplets and depolarized mitochondria, in the various pathological cell types relative to controls. These findings support the notion that macroautophagy is compromised in HD cells because autophagic vacuoles are unable to sequester abnormal or spent cellular components, resulting in cellular toxicity. Innovation in the treatment of this uniformly fatal disease may therefore depend on finding a way to help the autophagic machinery locate, sequester, and retain its cargo so it can be cleared from cells.

M. Martinez-Vicente et al., Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat. Neurosci. 13, 567–576 (2010). [Abstract]

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