亨廷顿病中的线粒体功能障碍：发病机制和治疗机会

Title:Mitochondrial Dysfunction in Huntington’s Disease: Pathogenesis and Therapeutic Opportunities

Volume: 22 Issue: 14

关键词: 亨廷顿病、线粒体、氧化应激、分子伴侣、活性氧、CAG。

摘要: Huntington’s disease (HD) is a prototypical neurodegenerative disease, preferentially disrupting the neurons of the striatum and cortex. Progressive motor dysfunctions, psychiatric disturbances, behavioral impairments, and cognitive decline are the clinical symptoms of HD progression. The disease occurs due to expanded CAG repeats in exon 1 of huntingtin protein (mHtt), causing its aggregation. Multiple cellular and molecular pathways are involved in HD pathology. Mitochondria, as vital organelles have an important role in most neurodegenerative diseases like HD. Over the years, the role of mitochondria in neurons has highly diverged; they not only contribute as a cell power source, but also as dynamic organelles that fragment and then fuse to attain a maximal bioenergetics performance, regulating intracellular calcium homeostasis, reactive oxygen species (ROS) generation, antioxidant activity and involved in apoptotic pathways. Indeed, these events are observed to be affected in HD, resulting in neuronal dysfunction in pre-symptomatic stages. MHtt causes critical transcriptional abnormality by altering the expression of a master co-regulator, peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), leading to increased susceptibility to oxidative stress and neuronal degeneration. Moreover, mHtt influences multiple cellular signaling events, which end with mitochondrial biogenesis. Here, we resume recent findings that pose mitochondria as an important regulatory organelle in HD and how mHtt affects mitochondrial function, trafficking and homeostasis and makes neurons prone to degeneration. Besides, we also uncover the mitochondrial-based potential targets and therapeutic approaches with imminent or currently ongoing clinical trials.

Cite this article as:

Mitochondrial Dysfunction in Huntington’s Disease: Pathogenesis and Therapeutic Opportunities, Current Drug Targets 2021; 22 (14) . https://dx.doi.org/10.2174/1389450122666210224105945