Chaperone-mediated autophagy

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Ana Maria Cuervo, Leonidas Stefanis, Ross Fredenburg, Peter Lansbury and David Sulzer (Science, 27 Aug 2004).

What happened

Cells have several disposal routes. In CMA, helper proteins (chaperones, including Hsc70) carry selected proteins to a receptor, LAMP2A, on the lysosome, which pulls them in for destruction. Cuervo et al. found that normal alpha-synuclein is broken down by CMA. The mutants A53T and A30P (landmark 4, 31) bound the receptor but were not taken in, which impaired their own breakdown and also blocked CMA of other proteins. In Alzforum comments at the time, John Trojanowski noted that the proteasome did not appear to be involved, and Mark Cookson read the paper as pointing to lysosomes over the proteasome and to raising Hsc70 as a way to lower synuclein (their readings, not results of the paper). Science 305(5688):1292-1295.

Human evidence followed: in postmortem brains from 7 people with Parkinson's, 6 with Alzheimer's and 8 controls, LAMP2A and Hsc70 were significantly lower in the substantia nigra and amygdala of the Parkinson's brains than in either other group. Cutting LAMP2A in a dopamine cell line reduced CMA activity and lengthened the half-life of synuclein (Alvarez-Erviti et al., University College London, Arch Neurol 2010). Later preclinical work reported that raising LAMP2A lowered synuclein and reduced its damage in cultured neurons and rat brain (summarised in Xilouri et al., Autophagy 2013).

Why it moved us toward a cure

It framed Parkinson's as partly a clearance failure and made the lysosome a therapeutic target, fitting the genetic links to GBA (landmark 16) and the GCase loop (landmark 35). Boosting CMA, rather than only lowering synuclein production (landmark 29), became an alternative strategy.

Outcome

Open. The mechanism is accepted as one clearance route, but no CMA-boosting drug has been found in the human Parkinson's trials covered by this map.

Sources

• Cuervo et al., Science 2004;305:1292-1295, DOI 10.1126/science.1101738, PMID 15333840 (abstract via Europe PMC) · Alzforum comments
• Alvarez-Erviti et al., Arch Neurol 2010;67:1464-1472, DOI 10.1001/archneurol.2010.198, PMID 20697033
• Xilouri et al., Autophagy 2013;9:2166-2168, DOI 10.4161/auto.26451, PMID 24145820 (short commentary; abstract says raising LAMP2A decreases synuclein)
• Not yet verified: whether later work confirms CMA failure in living patients; the status of any LAMP2A-targeted drug; the full text of Xilouri 2013 (only the abstract was read).