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Modulation of Mitophagy in Huntington Disease
Šonský, Ivan ; Hansíková, Hana (advisor) ; Kalous, Martin (referee)
Huntington diseases (HD) is a hereditary neurodegenerative disorder characterized by the presence of the aggregation prone mutated version of protein huntingtin (HTT). Mutation in huntingtin (mHTT) results in an aberrant expansion of the polyglutamine tract, thereby gaining toxic properties, which causes progressive loss of striatal medium spiny neurons. Neurons heavily rely on a healthy mitochondrial pool. Thereby, it is crucial to preserve biological mechanisms maintaining its turnover and quality control, such as mitophagy. However, mHTT impairs mitophagy, therefore preventing autophagosomes from engulfing mitochondria and resulting in an accumulation of dysfunctional mitochondria. Our recent results showed that mHTT-caused mitochondrial impairments can be observed in more easily accessible extraneuronal cells such as skin fibroblasts. While mitophagy is considered a fundamental cellular process, there is a lack of compounds selectively modulating mitophagy. Thereby, the aim of this diploma thesis was to introduce a small-molecule compound, MIND4-17, which showed neuroprotective effects in HD, and to study its selective effect on mitophagy in cultivated fibroblasts from HD patients and controls. Here we report that MIND4-17 increased the expression of specific autophagy markers in fibroblasts...
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Mitophagy in Huntington's Disease
Šonský, Ivan ; Hansíková, Hana (advisor) ; Macůrková, Marie (referee)
Mitochondrial dysfunctions contribute to the progression of many neurodegenerative diseases, including Huntington's disease (HD). In HD, mutation in the huntingtin gene (HTT) results in the expansion of CAG repeats, causing the growth of the polyglutamine tract. This growth is responsible for the gain of toxicity function of the protein. The turnover of dysfunctional and damaged mitochondria is mediated via mitophagy - a selective form of autophagy. Additionally, mitophagy impairments have recently been described to play a key role not only in neurodegenerative diseases. The protrusion of mitophagy results in the clustering of defective mitochondria, organelles which are responsible for fulfilling the energetic demands of neural cells. The most distinctive impact of the impairment is on the striatal medium spiny neurons and results in the development of motor and cognitive dysfunctions. This thesis describes how HD affects mitophagy and reveals the biggest obstacle of mitophagy - disruption of mitochondria targeting into emerging autophagosomes caused by the abnormal interaction of mHTT and p62. Induction of mitophagy at this stage could be crucial for the future therapeutic research of HD. Generally, initiation of mitophagy could become a relevant therapeutic target for many other...
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