Hypoxia and TTR dysregulation in astrocytes from Parkinson’s disease with a specific mitochondrial haplogroup: A single-cell analysis

Mitochondrial DNA variants have been linked to cognitive progression in Parkinson's disease; however, the mechanisms by which mitochondrial DNA variants or haplogroups contribute to this process remain unclear. In the present study, we analyzed single-nucleus RNA sequencing data from 241 post-mortem brain samples across five regions to investigate the dysregulatory mechanisms associated with mitochondrial DNA haplogroup H and haplogroups J, T, and U#. Our findings revealed significant alterations in the proportions of astrocyte subtypes CHI3L1 and GRM3 in the neocortical regions of haplogroup H. Notably, TTR was markedly downregulated in the dorsal motor nucleus of the Xth nerve region of patients with haplogroup H. Pathway analysis highlighted abnormal hypoxic and reactive oxygen species environments in astrocytes, whereas protein complex analysis revealed a consistent and significant elevation in ribosomal subunit complexes within the astrocyte subtypes. By constructing weighted and directed transcriptome-wide gene regulatory networks, we identified significant changes in transcription factor SP1 and homeobox protein HOXA5 activity in the astrocyte subtypes of individuals with haplogroup H. Additionally, widespread dysregulation was observed in the transcriptional control of TTR by multiple transcription factors. Parkinson's disease patients with haplogroup H also exhibited increased network functional connectivity in specific brain regions. This data-driven study underscores the potential mechanisms by which mitochondrial DNA haplogroups contribute to cognitive progression in Parkinson's disease, involving cellular composition changes, differential gene expression, pathway disruption, and gene regulatory networks. Our findings suggest that mitochondrial DNA haplogroup H may drive Parkinson's disease cognitive progression through aberrant TTR expression and a hypoxic environment.