Spatiotemporal analysis of soluble aggregates and autophagy markers in the R6/2 mouse model

Sci Rep. 2021 Jan 8;11(1):96. doi: 10.1038/s41598-020-78850-w.

Abstract

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 (HTT) aggregates in neurons bring 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 HTT 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 a known autophagy modulator, Nilotinib (Tasigna™), presently in clinical trials for PD, and HD, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Disease Models, Animal
  • Female
  • Humans
  • Huntingtin Protein / chemistry
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism*
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Huntington Disease / physiopathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / cytology
  • Neurons / metabolism
  • Protein Aggregates
  • Spatio-Temporal Analysis

Substances

  • Htt protein, mouse
  • Huntingtin Protein
  • Protein Aggregates