Abstract
White matter atrophy has been shown to precede the massive loss of striatal GABAergic neurons in Huntington’s disease (HD). This study investigated the effects of in vivo expression of reprogramming factor octamer-binding transcription factor 4 (OCT4) on neural stem cell (NSC) niche activation in the subventricular zone (SVZ) and induction of cell fate specific to the microenvironment of HD. R6/2 mice randomly received adeno-associated virus 9 (AAV9)-OCT4, AAV9-Null, or phosphate-buffered saline into both lateral ventricles at 4 weeks of age. The AAV9-OCT4 group displayed significantly improved behavioral performance compared to the control groups. Following AAV9-OCT4 treatment, the number of newly generated NSCs and oligodendrocyte progenitor cells (OPCs) significantly increased in the SVZ, and the expression of OPC-related genes and glial cell-derived neurotrophic factor (GDNF) significantly increased. Further, amelioration of myelination deficits in the corpus callosum was observed through electron microscopy and magnetic resonance imaging, and striatal DARPP32+ GABAergic neurons significantly increased in the AAV9-OCT4 group. These results suggest that in situ expression of the reprogramming factor OCT4 in the SVZ induces OPC proliferation, thereby attenuating myelination deficits. Particularly, GDNF released by OPCs seems to induce striatal neuroprotection in HD, which explains the behavioral improvement in R6/2 mice overexpressing OCT4.
Highlights
Huntington’s disease (HD) pathology caused by an expansion of the cytosine-adenineguanine (CAG) repeats within the HTT gene is characterized by massive loss of neurons in striatum and deep layers of the cortex as well as early and progressive thinning of white matter (WM) [1]
Previous studies have shown that the manifestation of clinical symptoms such as motor defects in HD is closely associated with early changes in WM with demyelination [5,12,13,14], suggesting that targeting oligodendrocyte could be therapeutic in HD
The associated virus 9 (AAV9)-octamer-binding transcription factor 4 (OCT4) group showed a significant increase in latency compared to the control groups in the accelerating speed rotarod test (4–40 rpm) at 6 weeks (PBS = 181.9 ± 19.5, AAV9-Null = 232.4 ± 16.8, AAV9-OCT4 = 246.7 ± 27.6 s), 8 weeks (PBS = 116.4 ± 16.8, AAV9-Null = 128.7 ± 16.2, AAV9-OCT4 = 179.2 ± 26.5 s), 13 weeks of age (PBS = 21.7 ± 4.6, AAV9-Null = 13.9 ± 4.1, AAV9-OCT4 = 57.4 ± 14.2 s) (Figure 2A) and constant speed rotarod test (12 rpm) at 10 weeks
Summary
Huntington’s disease (HD) pathology caused by an expansion of the cytosine-adenineguanine (CAG) repeats within the HTT gene is characterized by massive loss of neurons in striatum and deep layers of the cortex as well as early and progressive thinning of white matter (WM) [1]. WM changes can be observed in the striatum nearby the corpus callosum (CC), and in the posterior WM tracts at a pre-symptomatic (pre-HD) stage [1,2,3,4,5,6]. Previous studies have shown that the manifestation of clinical symptoms such as motor defects in HD is closely associated with early changes in WM with demyelination [5,12,13,14], suggesting that targeting oligodendrocyte could be therapeutic in HD. A recent study reported that reduction of the mHTT in oligodendrocytes prevented behavioral deficits and demyelination in HD mice [15]. Chronic demyelination in HD at late-symptomatic (late-HD) stage can be occurred by the malfunction of oligodendrocytes and myelinating repair system [16]
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