Mitochondrial health is important in ageing and dysfunctional oxidative phosphorylation (OXPHOS) accelerates ageing and influences neurodegeneration. Mitochondrial DNA (mtDNA) codes for vital OXPHOS subunits and mtDNA background has been associated with neurodegeneration; however, no study has characterised mtDNA variation in Progressive supranuclear palsy (PSP) or Corticobasal degeneration (CBD) risk or pathogenesis. In this case–control study, 910 (42.6% male) neurologically-healthy controls, 1042 (54.1% male) pathologically-confirmed PSP cases, and 171 (52.0% male) pathologically-confirmed CBD cases were assessed to determine how stable mtDNA polymorphisms, in the form of mtDNA haplogroups, were associated with risk of PSP, risk of CBD, age of PSP onset, PSP disease duration, and neuropathological tau pathology measures for neurofibrillary tangles (NFT), neuropil threads (NT), tufted astrocytes (TA), astrocytic plaques (AP), and oligodendroglial coiled bodies (CB). 764 PSP cases and 150 CBD cases had quantitative tau pathology scores. mtDNA was genotyped for 39 unique SNPs using Agena Bioscience iPlex technologies and mitochondrial haplogroups were defined to mitochondrial phylogeny. After adjustment for multiple testing, we observed an association with risk of CBD for mtDNA sub-haplogroup H4 (OR = 4.51, P = 0.001) and the HV/HV0a haplogroup was associated with a decreased severity of NT tau pathology in PSP cases (P = 0.0023). Our study reports that mitochondrial genomic background may be associated with risk of CBD and may be influencing tau pathology measures in PSP. Replication of these findings will be important.

中文翻译：

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线粒体基因组变异与皮质基底节变性、进行性核上性麻痹和神经病理学 tau 蛋白测量的关联。

线粒体健康对于衰老非常重要，氧化磷酸化 (OXPHOS) 功能失调会加速衰老并影响神经退行性变。重要 OXPHOS 亚基的线粒体 DNA (mtDNA) 编码和 mtDNA 背景与神经退行性疾病有关；然而，尚无研究描述进行性核上性麻痹 (PSP) 或皮质基底节变性 (CBD) 风险或发病机制中 mtDNA 变异的特征。在这项病例对照研究中，评估了 910 例（42.6% 男性）神经健康对照、1042 例（54.1% 男性）病理确诊的 PSP 病例和 171 例（52.0% 男性）病理确诊的 CBD 病例，以确定 mtDNA 多态性的稳定性以 mtDNA 单倍群的形式，与 PSP 风险、CBD 风险、PSP 发病年龄、PSP 疾病持续时间以及神经原纤维缠结 (NFT)、神经纤维丝 (NT)、簇状星形胶质细胞 (TA) 的神经病理学 tau 病理学测量相关）、星形胶质细胞斑块（AP）和少突胶质细胞卷曲体（CB）。764 例 PSP 病例和 150 例 CBD 病例有定量 tau 病理评分。使用 Agena Bioscience iPlex 技术对 mtDNA 的 39 个独特 SNP 进行基因分型，并将线粒体单倍群定义为线粒体系统发育。经过多次测试调整后，我们观察到 mtDNA 亚单倍群 H4 与 CBD 风险相关（OR = 4.51，P = 0.001），并且 HV/HV0a 单倍群与 PSP 病例中 NT tau 病理严重程度降低相关（P = 0.0023）。我们的研究报告称，线粒体基因组背景可能与 CBD 风险相关，并可能影响 PSP 中的 tau 病理学测量。重复这些发现非常重要。