Upregulated chaperone-mediated autophagy may reduce cancer incidence in Huntington’s disease

What is it about?

Huntington’s disease (HD) is an inherited neurodegenerative disease caused by a mutation, a CAG repeat expansion in a specific gene, leading to an expanded poly-glutamine sequence in the huntingtin protein. Clinically, the patients’ neurological symptoms are due to dysfunction of specific neurons in the brain. It has been known for about 25 years that patients with HD have a markedly reduced risk of cancer of almost all types. The cellular and molecular background for the reduced cancer incidence is so far unknown, but autophagy could play an important role. Misfolded proteins like the expanded huntingtin are normally cleared from the cells by autophagy. Several types of autophagy work to clean up in our cells, but one specific type, the chaperone-mediated autophagy, CMA, is particularly active in cells from HD patients. Recently, CMA is also assumed to play a key role in prevention of cellular transformation of normal cells into cancer cells. Based on these observations supplied with thorough studies of the literature I present the hypothesis: CMA activation in cells from carriers of the HD mutation protects them from carcinogenesis.

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Why is it important?

To understand the biological process it is important knowledge that a well-defined group of patients presents compelling cancer protecting mechanisms. It is also important that the protecting mechanisms take place in several, maybe all, cell types and work early in life even before onset of the first neurological symptoms. Furthermore, CAG expansion mutations occur in other genes unrelated to HD resulting in neurodegenerative diseases with similar accumulation of disease specific proteins in the cells and significantly reduced cancer incidence. It is very important that the role of CMA in cell cycle control and anti-tumor function is an increasingly hot topic in cancer research.

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