Neural stem cells derived from the developing forebrain of YAC128 mice exhibit pathological features of Huntington's disease.

OBJECTIVES

Huntington's disease (HD) is a devastating neurodegenerative disease caused by polyglutamine (polyQ) expansion in the huntingtin (HTT) gene. Mutant huntingtin (mHTT) is the main cause of HD and is associated with impaired mitochondrial dynamics, ubiquitin-proteasome system and autophagy, as well as tauopathy. In this study, we aimed to establish a new neural stem cell line for HD studies.

MATERIALS AND

METHODS

YAC128 mice are a yeast artificial chromosome (YAC)-based transgenic mouse model of HD. These mice express a full-length human mutant HTT gene with 128 CAG repeats and exhibit various pathophysiological features of HD. In this study, we isolated a new neural stem cell line from the forebrains of YAC128 mouse embryos (E12.5) and analysed its characteristics using cellular and biochemical methods.

RESULTS

Compared to wild-type (WT) NSCs, the YAC128 NSC line exhibited greater proliferation and migration capacity. In addition to mHTT expression, increased intracellular Ca2+ levels and dysfunctional mitochondrial membrane potential were observed in the YAC128 NSCs. YAC128 NSCs had defects in mitochondrial dynamics, including a deficit in mitochondrial axonal transport and unbalanced fusion and fission processes. YAC128 NSCs also displayed decreased voltage response variability and Na+ current amplitude. Additionally, the ubiquitin-proteasome and autophagy systems were impaired in the YAC128 NSCs.

CONCLUSIONS

We have established a new neural stem line from YAC128 transgenic mice, which may serve as a useful resource for studying HD pathogenesis and drug screening.