Polyglutamine disorders are neurodegenerative diseases that share a CAG repeat expansion in the coding region, resulting in aggregated proteins that can be only degraded through aggrephagy. We measured the expression of autophagy genes in peripheral blood mononuclear cells of 20 patients with Huntington's disease (HD), 20 with spinocerebellar ataxia type 2 (SCA2), and 20 healthy individuals. HD patients showed increased expression of MAP1LC3B (+ 43%; p = 0.048), SQSTM1 (+ 49%; p = 0.002), and WDFY3 (+ 89%; p < 0.001). SCA2 patients had increased expression of WDFY3 (+ 69%; p < 0.001). We show that peripheral markers of autophagy are elevated in polyQ diseases, and this is particularly evident in HD.

Increasing findings suggest that demyelination may play an important role in the pathophysiology of brain injury, but the exact mechanisms underlying such damage are not well known. Mechanical tensile strain of brain tissue occurs during traumatic brain injury. Several studies have investigated the cellular and molecular events following a static tensile strain of physiological magnitude on individual cells such as oligodendrocytes. However, the pathobiological impact of high-magnitude mechanical strain on oligodendrocytes and myelinated fibers remains under investigated. In this study, we reported that an applied mechanical tensile strain of 30% on mouse organotypic culture of cerebellar slices induced axonal injury and elongation of paranodal junctions, two hallmarks of brain trauma. It was also able to activate MAPK-ERK1/2 signaling, a stretch-induced responsive pathway. The same tensile strain applied to mouse oligodendrocytes in primary culture induced a profound damage to cell morphology, partial cell loss, and a decrease of myelin protein expression. The lower tensile strain of 20% also caused cell loss and the remaining oligodendrocytes appeared retracted with decreased myelin protein expression. Finally, high-magnitude tensile strain applied to 158N oligodendroglial cells altered myelin protein expression, dampened MAPK-ERK1/2 and MAPK-p38 signaling, and enhanced the production of reactive oxygen species. The latter was accompanied by increased protein oxidation and an alteration of anti-oxidant defense that was strain magnitude-dependent. In conclusion, mechanical stretch of high magnitude provokes axonal injury with significant alterations in oligodendrocyte biology that could initiate demyelination. Electronic supplementary material The online version of this article (10.1007/s12035-018-1372-6) contains supplementary material, which is available to authorized users.