Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterised by the abnormal expansion of the CAG trinucleotide repeat in the Huntingtin gene (HTT). The HTT gene encodes an approximately 348 kDa Huntingtin (HTT) protein with a normal 23 glutamine repeat at the N-terminus. Mutant HTT (mHTT) containing more than 40 poly-glutamine repeat leads to neurodegeneration in HD patients, often diagnosed with involuntary motor deficits. Clearance of mHTT is found to rely on the autophagy pathway due to the size of fibril aggregates. Autophagy is essential for maintaining cellular homeostasis and protein quality control, and the polarisation of neurons requires compartmentalised regulation of autophagy in distal areas. Recent study indicated autophagosome transport is i...[ Read more ]

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterised by the abnormal expansion of the CAG trinucleotide repeat in the Huntingtin gene (HTT). The HTT gene encodes an approximately 348 kDa Huntingtin (HTT) protein with a normal 23 glutamine repeat at the N-terminus. Mutant HTT (mHTT) containing more than 40 poly-glutamine repeat leads to neurodegeneration in HD patients, often diagnosed with involuntary motor deficits. Clearance of mHTT is found to rely on the autophagy pathway due to the size of fibril aggregates. Autophagy is essential for maintaining cellular homeostasis and protein quality control, and the polarisation of neurons requires compartmentalised regulation of autophagy in distal areas. Recent study indicated autophagosome transport is impaired in HD, but the underlying mechanism is poorly understood. In this study, by cross-breeding a Huntington’s Disease mouse model (zQ175KI) with transgenic GFP-LC3 mouse, I investigated the autophagosome trafficking dynamics in primary striatal neurons using live cell imaging. Retrograde transport disruption was observed in HD autophagosomes, including reduced travelling speed and abrupted pausing. To better understand the underlying mechanism of these defects, I investigated the CDK5 Lis1/Ndel1/Dynein pathway and microtubule stability. The level of CDK5 activator p25 was increased in aged HD mouse brains but changes were insignificant in vitro. Pharmacological treatments of roscovitine (CDK inhibitor) and taxol (microtubule stabilising agent) were unable to rescue autophagosome trafficking defects in HD, though the effects of CDK5 inhibition in HD were more heterogenous compared to wild-type. Further investigation showed that transport disruption was not a global cargo defect but specific to autophagosomes.