THESIS
2021
1 online resource (viii, 62 pages) : illustrations (some color)
Abstract
Huntington's Disease (HD) is a progressive autosomal neurodegenerative disorder. HD is caused by an abnormal expansion of CAG repeat at the N-terminus ofHuntingtin gene ( HTT), which encodes huntingtin protein with around 348kDa. HD patients with over 40 CAG repeats in HTT exon 1 suffer from significant cognitive and motor deterioration. Pathogenesis studies in HD implicate the preceding molecular dysregulation and neuron loss before the clinical diagnosis of HD, highlighting the importance in understanding function of mutant huntingtin protein (mHTT) in the early stage of HD to find potential therapeutic targets for HD. However, the role of mitochondrial transport in striatal neurons (the most vulnerable neurons in HD) is poorly understood. In this study, I investigated the axonal mito...[
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Huntington's Disease (HD) is a progressive autosomal neurodegenerative disorder. HD is caused by an abnormal expansion of CAG repeat at the N-terminus ofHuntingtin gene ( HTT), which encodes huntingtin protein with around 348kDa. HD patients with over 40 CAG repeats in HTT exon 1 suffer from significant cognitive and motor deterioration. Pathogenesis studies in HD implicate the preceding molecular dysregulation and neuron loss before the clinical diagnosis of HD, highlighting the importance in understanding function of mutant huntingtin protein (mHTT) in the early stage of HD to find potential therapeutic targets for HD. However, the role of mitochondrial transport in striatal neurons (the most vulnerable neurons in HD) is poorly understood. In this study, I investigated the axonal mitochondria transport in cultured striatal neurons from a transgenic HD mouse model (zQI75KI mice) using real-time imaging. I observed region-specific alterations of mitochondrial transport in cultured striatal neurons of HD mice; retrograde mitochondria transport in HD was altered at proximal axon including increased average velocity and frequency of reversal, coincident with fragmented mitochondria at this region. At mid-axonal region, average velocity and processive movement of anterograde mitochondria decreased in HD striatal neurons. To understand the underlying mechanism of altered mitochondria transport in HD striatal neurons, we further explore whether over-expressing two mHTT interacting proteins, Metaxin-1 (MTX-1) and Miro-1 can rescue the altered axonal mitochondrial transport in striatal neurons of HD mice. Restored anterograde average velocity and travel length of axonal mitochondria was observed in HD striatal neurons with over-expression of Miro-1. While less effect was seen in mitochondria transport in HD when over-expressed MTX-1 in striatal neurons. Therefore, the potential rescue effect of Miro-1 on mitochondria transport in HD striatal neurons is proposed, although further investigations on the role of Miro-1 in HD are needed.
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