Huntington’s disease (HD) is a genetic disorder caused by mutations in the huntingtin gene. The altered huntingtin protein (htt) causes gradual neurological damage; HD usually develops between the ages of 30 and 50 and symptoms get worse over the next 20 or more years. Defects in macroautophagy – a lysosomal system for removing toxic and unwanted proteins – have been suggested to play a role in the cell’s inability to clear mutant htt, but the exact mechanisms are poorly understood.
Researchers at the Albert Einstein College of Medicine have now shown that mutant htt interferes directly with the function of the autophagosome. Normally, cellular debris is sequestered in double-membraned autophagosomes and delivered to lysosomes for degradation following fusion of the vesicles. In cells from two mouse models of HD and in cells from people with the disease, fusion of the two vesicles and enzymatic activity of the lysosome were unaffected but mutant htt was found to stick to the inner membrane of the autophagosome and prevent normal loading of proteins destined for recycling. As a result, the autophagosomes are empty when they arrive at the lysosomes and cellular debris accumulates and probably contributes to cell death. Although defects in autophagy have been linked to other neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, the researchers believe that the defect in cargo loading seen in the present study has not been described before.
The study, which is published in Nature Neuroscience, also suggests that proposed treatments for HD which involve activating lysosomes are unlikely to be effective. Professor Ana Maria Cuervo, the senior author of the study, likened autophagosomes to ‘garbage bags’ and lysosomes to ‘garbage trucks’ – there is no point in more trucks if the bags are not being filled.