Abstract
Background: White matter atrophy has been shown to precede the massive loss of striatal GABAergic neurons in Huntington’s disease (HD). The HD-induced white matter atrophy is associated with motor deficits. In vivo reprogramming toward a plastic state has emerged as a new approach for treating neurological diseases. Particularly, octamer-binding transcription factor 4 (OCT4) can induce myelin repair and functional recovery. This study investigated the effects of in situ expression of reprogramming factor OCT4 on behavioral performances, neural stem cell (NSC) niche activation in the subventricular zone (SVZ) and induction of cell fate specific to the changed microenvironment of HD. Methods: R6/2 mice, a transgenic mouse model of HD, randomly received adeno-associated virus serotype 9 (AAV9)-OCT4, AAV9-Null, or phosphate-buffered saline in both lateral ventricles at 4 weeks of age. To evaluate the behavioral improvement, rotarod test and grip strength test were performed at regular intervals. To investigate the expression of oligodendrocyte progenitor cell (OPC)-related genes, real-time quantitative reverse transcription PCR (qRT-PCR) and immunohistochemistry were performed. Next, we assessed the amelioration of myelination deficits via transmission electron microscope (TEM) and magnetic resonance imaging (MRI) at 13 weeks of age. Finally, we confimed striatal neuroprotecion by qRT-PCR and confocal microscopy.Results: The AAV9-OCT4 group displayed significantly improved rotarod performance and grip strength compared to the control groups. Following AAV9-OCT4 treatment, the number of newly generated NSCs and OPCs was significantly increased in the SVZ, and the expression of OPC-related genes such as NG2, Olig2, PDGFRα, Wnt3 and myelin regulatory factor (MYRF), and glial cell-derived neuroprotective factor (GDNF) was significantly increased. Further, the amelioration of myelination deficits in the corpus callosum was observed through TEM and MRI, and striatal DARPP32+ GABAergic neurons significantly increased in the AAV9-OCT4 group.
Voluntary saccade inhibition deficits correlate with extended white-matter cortico-basal atrophy in Huntington's disease