Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Acta Neuropathol. 2022 Jun;143(6):687-695. doi: 10.1007/s00401-022-02423-6. Epub 2022 Apr 30.
Frontotemporal lobar degeneration (FTLD) is a common cause of young onset dementia and is characterised by focal neuropathology. The reasons for the regional neuronal vulnerability are not known. Mitochondrial mechanisms have been implicated in the pathogenesis of FTLD, raising the possibility that frontotemporal regional mutations of mitochondrial DNA (mtDNA) are contributory causes. Here we applied dual sequencing of the entire mtDNA at high depth to identify high-fidelity single nucleotide variants (mtSNVs) and mtDNA rearrangements in post mortem brain tissue of people affected by FTLD and age-matched controls. Both mtSNVs and mtDNA rearrangements were elevated in the temporal lobe, with the greatest burden seen in FTLD. mtSNVs found in multiple brain regions also reached a higher heteroplasmy levels in the temporal lobe. The temporal lobe of people with FTLD had a higher burden of ribosomal gene variants predicted to affect intra-mitochondrial protein synthesis, and a higher proportion of missense variants in genes coding for respiratory chain subunits. In conclusion, heteroplasmic mtDNA variants predicted to affect oxidative phosphorylation are enriched in FTLD temporal lobe, and thus may contribute to the regional vulnerability in pathogenesis.
额颞叶变性（FTLD）是年轻发病痴呆的常见原因，其特征为局灶性神经病理学改变。导致区域性神经元易损性的原因尚不清楚。线粒体机制已被牵涉到 FTLD 的发病机制中，这增加了额颞叶区域线粒体 DNA（mtDNA）突变是促成原因的可能性。在这里，我们应用高深度的整个 mtDNA 双重测序来鉴定受 FTLD 影响的人和年龄匹配的对照者死后脑组织中的高保真单核苷酸变异（mtSNV）和 mtDNA 重排。mtSNV 和 mtDNA 重排都在颞叶中升高，FTLD 中可见最高的负担。在多个脑区发现的 mtSNV 也在颞叶中达到了更高的异质性水平。FTLD 患者的颞叶携带核糖体基因变异的负担更高，这些变异预计会影响线粒体内部蛋白质合成，并且编码呼吸链亚基的基因中的错义变异比例更高。总之，预计会影响氧化磷酸化的异质性 mtDNA 变异在 FTLD 颞叶中富集，因此可能有助于发病机制中的区域性易损性。
