期刊
FASEB JOURNAL
卷 34, 期 6, 页码 8139-8154出版社
WILEY
DOI: 10.1096/fj.201902277RR
关键词
aggregation; Huntington's; mitochondria; model; respiration
资金
- Takeda Pharmaceutical Company (Takeda Pharmaceutical Co., Ltd.)
- RCUK \ Medical Research Council (MRC) [MR/L02053X/1, MR/M02492X/1, MC_U12266B]
- MRC [UKDRI-1008/1, MR/M02492X/1, MR/L02053X/1, UKDRI-1008/2, MR/K023268/1] Funding Source: UKRI
Robust cellular models are key in determining pathological mechanisms that lead to neurotoxicity in Huntington's disease (HD) and for high throughput pre-clinical screening of potential therapeutic compounds. Such models exist but mostly comprise non-human or non-neuronal cells that may not recapitulate the correct biochemical milieu involved in pathology. We have developed a new human neuronal cell model of HD, using neural stem cells (ReNcell VM NSCs) stably transduced to express exon 1 huntingtin (HTT) fragments with variable length polyglutamine (polyQ) tracts. Using a system with matched expression levels of exon 1 HTT fragments, we investigated the effect of increasing polyQ repeat length on HTT inclusion formation, location, neuronal survival, and mitochondrial function with a view to creating an in vitro screening platform for therapeutic screening. We found that expression of exon 1 HTT fragments with longer polyQ tracts led to the formation of intra-nuclear inclusions in a polyQ length-dependent manner during neurogenesis. There was no overt effect on neuronal viability, but defects of mitochondrial function were found in the pathogenic lines. Thus, we have a human neuronal cell model of HD that may recapitulate some of the earliest stages of HD pathogenesis, namely inclusion formation and mitochondrial dysfunction.
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