Mitochondrial and autophagosomes' transport defect in Q175 knock-in mouse model of huntington's disease

Abstract

Huntington’s disease (HD) is an autosomal genetic neurodegenerative disorder caused by the expansion of CAG in the huntingtin gene. Mutated Huntingtin proteins induce neuronal death in cortex and striatum regions followed by other brain regions. Mitochondrial and autophagy dysfunctions are thought to be a key pathogenic mechanism of HD. However, the neuritic transport of mitochondria and autophagosomes in HD primary neurons is not clearly understood yet. Our data indicated that the spatial distributions of mitochondria were affected in HD/GFP-mt crossed mice. Furthermore, the real-time live-cell imaging data showed that the percentage of moving mitochondria via neurites significantly decreased in HD neurons in an age dependent manner, and also mitochondrial transport behavior was spatially and temporally regulated in both wild type WT and HD of primary cortical and striatal neurons. Mitochondria in the proximal, middle and distal region had different transport patterns in different neuronal development stages, and they were distinctively affected in the primary cortical and striatal neurons of HD. Additionally, more small moving mitochondria, whose transport behavior was significantly different from large moving mitochondria, existed in HD with an age-dependent manner, indicating that mitochondria were under more stress condition in HD. The autophagosome data showed that neuritic swelling existed in some of HD cortical neurons at basal level. Moving autophagosomes had lower speed in the transition stage from young stage to mature stage in HD cortical neurons, while striatal moving autopahgosomes showed higher speed in the same stage in HD. Also, the moving autophagosomes’ transport was differently regulated in different neuronal stages and regions at basal level. Taken together, mitochondrial and autophagosomes’ transport were altered in both striatal and cortical neurons of HD, which implied mitochondria and autophagosomes as potential therapeutic targets of HD. Key words: Huntington’s disease, mitochondria, autophagosomes, real-time live-cell imaging

Date of Award	2017
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology