PT  - JOURNAL ARTICLE
AU  - Dagmar E Ehrnhoefer
AU  - Dale DO Martin
AU  - Xiaofan Qiu
AU  - Safia Ladha
AU  - Nicholas S Caron
AU  - Niels H Skotte
AU  - Yen TN Nguyen
AU  - Sabine Engemann
AU  - Sonia Franciosi
AU  - Michael R Hayden
TI  - Feeding schedule and proteolysis regulate autophagic clearance of mutant huntingtin
AID  - 10.1101/116178
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 116178
4099  - http://biorxiv.org/content/early/2017/03/13/116178.short
4100  - http://biorxiv.org/content/early/2017/03/13/116178.full
AB  - The expression of mutant huntingtin (mHTT) causes Huntington disease (HD), and lowering its levels is therefore an attractive therapeutic strategy. Here we show that scheduled feeding significantly decreases mHTT protein levels through enhanced autophagy in the CNS of an HD mouse model, while short term fasting is sufficient to observe similar effects in peripheral tissue. Furthermore, preventing proteolysis at the caspase-6 cleavage site D586 (C6R) makes mHTT a better substrate for autophagy, additionally increasing its clearance. Mice expressing mutant C6R also exhibit increased autophagy at baseline compared to an HD model with cleavable mHTT, suggesting that the native function of HTT in promoting autophagy is disrupted upon cleavage and re-established by prevention of cleavage by caspase-6. In HD patients, mHTT clearance and autophagy may therefore become increasingly impaired as a function of age and disease stage by gradually increased activity of mHTT-processing enzymes.