The Differential Profiling of Ubiquitin‐Proteasome and Autophagy Systems in Different Tissues before the Onset of Huntington's Disease Models

Abstract

Huntington's disease (HD) is a genetic and neurodegenerative disease, leading to motor and cognitive dysfunction in HD patients. At cellular level, this disease is caused by the accumulation of mutant huntingtin (HTT) in different cells, and finally results in the dysfunction of different cells. To clean these mutant proteins, ubiquitin-proteasome system (UPS) and autophagy system are two critical pathways in the brain; however, little is known in other peripheral tissues. As mutant HTT affects different tissues progressively and might influence the UPS and autophagy pathways at early stages, we attempted to examine two clearance systems in HD models before the onset. Here, in vitro results showed that the accumulation of UPS signals with time was observed obviously in neuroblastoma and kidney cells, not in other cells. In HD transgenic mice, we observed the impairment of UPS, but not autophagy, over time in the cortex and striatum. In heart and muscle tissues, disturbance of autophagy was observed, whereas dysfunction of UPS was displayed in liver and lung. These results suggest that two protein clearance pathways are disturbed differentially in different tissues before the onset of HD, and enhancement of protein clearance at early stages might provide a potential stratagem to alleviate the progression of HD.

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing

“…While LAMP2A and Hsc70 are upregulated in early HD to compensate for decreased ALN clearance, CMA eventually fails in parallel with neuronal loss 47,96 . The status of the UPS in HD is currently unclear, but it only poorly cleaves mutant forms of Htt (and other polyglutamine tracts), while animal models suggest that it is impaired in HD [which would further lead to reduced clearance of Htt 97 .…”

The regulatory roles of microRNAs toward pathogenesis and treatments in Huntington's disease

“…Based on previous studies, several different neurodegenerative diseases show poor treatments due to loss of functions in these two systems [ 29 , 30 ]. In HD, mHTT has been reported to be degraded slowly, and impairment of two protein degradation systems has been found in different HD models [ 17 , 31 – 34 ]. For example, a deficiency of a unique α-amine E2 enzyme, UBE2W, is highly correlated with the accumulation of mHTT [ 35 ], and polyQ of mHTT has been shown to block the activity of proteasomes [ 36 ], indicating the impairment of the UPS system in HD.…”

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

“…HD also modulates the function of autophagy [128][129][130][131][132], although certain studies suggest that the two protein clearance pathways are impaired differently in different tissue types before the onset of HD [133]. In addition, cross-talk between the proteasome and autophagy pathways seems to be affected in HD.…”