Although our current study points toward the possibility that the defective protein turnover may contribute to the A-T neurodegeneration, it does not rule out the possibility that the defective DNA repair may also contribute to A-T pathology (neurodegeneration).
As defective protein turnover in neurons has been a hallmark of many neurological diseases [36] [41], our results point to the possibility for the first time that ISG15-mediated impairment of protein degradation in A-T neurons could contribute to the progressive neurodegeneration in A-T patients.
Hydrocephalus is the main central nervous system disorder associated with defective CSF turnover [ 3, 6].
However, in the majority of cases, the presence of giant mitochondria is a consequence of defective mitochondrial turnover (15, 46).
In order to establish whether defective organelle turnover in gba −/− cells had a direct impact on mitochondrial volume in cells, we assayed mitochondrial mass using confocal microscopy.
This model describes defective actin turnover during stress due to the polyglutamine expansion in huntingtin causing ER disruption, increased calcium levels and activation of TG2, resulting in aberrant cofilin actin covalent cross-links.
Although this is the first report of defective actin turnover via cofilin in HD, several previous studies have reported beneficial effects of the Rho-associated kinase (ROCK) inhibitor, Y-27632, in HD model systems (61).
Therefore, the reduced ability of these cells to free up ATP during stress or defective actin turnover, even subtly, would conceivably lead to the changes in spine density, axonal atrophy and eventual neurodegeneration, all observed in MSNs in HD.
Hydrocephalus is a central nervous system disorder associated with defective CSF turnover, and AQP4 is a water channel located in the areas described above associated with the elimination of cerebral edema [ 3, 6].
