Abstract:
In our studies we have chosen mutant huntingtin (mHTT) protein as a cargo to study
aggrephagy, where an expansion of the polyglutamine (polyQ) tract in its N-terminus leads
to aggregation and is a cause of Huntington’s disease (HD). It is a unique cargo to study
aggrephagy as all the cases of HD are attributed to the mutation or polyQ expansion in the
single gene coding for HTT protein. Since cargo (mHTT) recognition failure has been
reported in HD, it becomes intriguing to understand the incompetency of autophagy
adaptors to recognize and capture mutant huntingtin (mHTT) aggregates which culminates
in ineffective clearance of the same.
In an attempt to address some of the above mentioned questions, we established a cellular
model of HD wherein we studied aggregation of mHTT, its subcellular localization and its
effects on basal autophagy.
We also studied the role of autophagy induction on clearance of mHTT aggregates by
boosting autophagy with a known small molecule autophagy inducer Torin1. This proofof-principle study reiterates the importance of autophagy induction on increased
recognition, capture and subsequent degradation of mHTT. In addition, towards this
objective, we are developing a cell-based temporal model for aggrephagy to study the
dynamics of mutant huntingtin aggregate formation and its interaction with the autophagy
machinery. Future directions of this work would be to get more insights into the
aggrephagy mechanism.
