Year: 2024
Type: conference-abstract
Abstract: Background Selective neurodegeneration in the striatum is prominent in Huntington’s disease (HD). However, the specific vulnerability of the striatum is not fully understood. HD has been traditionally studied through a neuro-centric perspective. Nonetheless, astrocytes also express mutant Huntingtin (mHTT) and exhibit impaired metabolism. This suggests that mHTT may cause neuronal dysfunction through non-cell autonomous alterations. One of the proposed mechanisms is a dysregulation of mitochondrial quality control mechanisms (MQCM), which has already been described in striatal neurons. Aims To examine whether mHtt expression in striatal astrocytes interferes with MQCM. We focused on the PINK1-Parkin mitophagy pathway in the R6/1 model of HD. Methods Striatal astrocytes in primary cell cultures were treated with Bafilomycin A1 (Bafa1+) to analyze mitophagy proteins. Concurrently, ACSA2+ astrocytes were isolated from adult mice and mitophagy protein levels and expression were evaluated. Results p62 protein levels were significantly increased in R6/1 astrocytes treated with Bafa1+ and DMSO without changes in levels of LC3II (a marker of activation of autophagy). There was also a higher colocalization of p62 with the mitochondrial marker TOMM20 in R6/1 striatal astrocytes treated with Bafa1+ and DMSO. In isolated ACSA2+ astrocytes from adult R6/1 mice, p62 protein levels were increased in 12- and 20-week-old astrocytes, whereas LC3 was significantly decreased in 20-week-old astrocytes. Conclusions Our results suggest that the mitophagy pathway is stuck at p62 accumulation in striatal astrocyte mitochondria in the R6/1 model of HD. Future studies should examine how other parts of the PINK1-Parkin pathway are affected and whether these alterations play a role in neuronal degeneration.
Authors: Alba Pereda, Laura López-Molina, Sílvia Ginés
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402374590