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.
Keywords: Huntington's disease (HD); autophagy; protein clearance; transgenic mice; ubiquitin-proteasome system.
© 2014 International Society of Neuropathology.