Dysregulated autophagy in neurodegenerative diseases
Maintenance of cellular proteostasis is vital for post-mitotic cells
like neurons to sustain normal physiological function and homeostasis,
defects in which are established hallmarks of several age-related
conditions like AD, PD, HD and ALS. The spatio-temporal accumulation of
aggregated proteins in the form of inclusion bodies/plaques is one of
the major characteristics of many neurodegenerative diseases, including
Huntington’s disease (HD). Toxic accumulation of HUNTINGTIN aggregates
in neurons brings about the aberrant phenotypes of HD, including severe
motor dysfunction, dementia and cognitive impairment at the organismal
level, in an age-dependent manner. In several cellular and animal
models, aggrephagy induction has been shown to clear aggregate-prone
proteins like HUNTINGTIN and ameliorate disease pathology by conferring
neuroprotection. In this study, we used the mouse model of HD, R6/2, to
understand the pathogenicity of mHTT aggregates, primarily focusing on
autophagy dysfunction. We report that basal autophagy is not altered in
R6/2 mice, whilst being functional at a steady-state level in neurons.
Moreover, we tested the efficacy of Nilotinib (TasignaTM) in
curbing mHTT aggregate growth and their potential clearance, which was
ineffective in both inducing autophagy and rescuing the pathological
phenotypes in R6/2 mice.