A030 Exploring mitophagy alterations in striatal astrocytes in Huntington’s disease

<h3>Background</h3> 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. <h3>Aims</h3> 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. <h3>Methods</h3> 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. <h3>Conclusions</h3> 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.