Abstract
Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by the expansion of polyglutamine (polyQ) tract that leads to motor, cognitive and psychiatric impairment. Currently there is no cure for HD. A transgenic HD nonhuman primate (HD-NHP) model was developed with progressive development of clinical and pathological features similar to human HD, which suggested the potential preclinical application of the HD-NHP model. Elevated expression of miR-196a was observed in both HD-NHP and human HD brains. Cytotoxicity and apoptosis were ameliorated by the overexpression of miR-196a in HD-NHP neural progenitor cells (HD-NPCs) and differentiated neural cells (HD-NCs). The expression of apoptosis related gene was also down regulated. Mitochondrial morphology and activity were improved as indicated by mitotracker staining and the upregulation of CBP and PGC-1α in HD-NPCs overexpressing miR-196a. Here we demonstrated the amelioration of HD cellular phenotypes in HD-NPCs and HD-NCs overexpressing miR-196a. Our results also suggested the regulatory role of miR-196a in HD pathogenesis that may hold the key for understanding molecular regulation in HD and developing novel therapeutics.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of CAG trinucleotide repeats located at the first exon of the HTT gene [1,2,3,4]
Expression of miR-196a and mutant HTT (mHTT) transgene in HD1 and HD7-NHP striatum were measured by quantitative RT-PCR (qPCR) (Fig 1A and 1B) and both exhibited higher expression levels when compared to the WT-NHP (Fig 1A and 1B)
Upregulation of miR-196a was observed in undifferentiated pluripotent stem cells (PSCs), NPCs, and NCs derived from HD nonhuman primate (HD-NHP) when compared to the controls (Fig 1D)
Summary
HD is an autosomal dominant neurodegenerative disorder caused by the expansion of CAG trinucleotide repeats located at the first exon of the HTT gene [1,2,3,4]. A core component in disease pathogenesis and progression, has been investigated by transcriptomic and small RNA profiling approaches [10,11,12,13,14]. Dysregulation of genes and non-coding RNA such as micro RNAs (miRNAs) in the brain are highly correlated with neuropathological changes in diseases such as HD [13,15,16,17,18,19,20,21,22]. Dysregulated expression of peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α (PGC-1α), a regulator of mitochondrial biogenesis and PLOS ONE | DOI:10.1371/journal.pone.0162788. Dysregulated expression of peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α (PGC-1α), a regulator of mitochondrial biogenesis and PLOS ONE | DOI:10.1371/journal.pone.0162788 September 15, 2016
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