Computational Neuroimaging Group, Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain.
Biomedical Research Doctorate Program, University of the Basque Country (UPV/EHU), Leioa, Spain.
Neuropathol Appl Neurobiol. 2021 Dec;47(7):1092-1108. doi: 10.1111/nan.12725. Epub 2021 May 17.
To delineate the neurogenetic profiles of brain degeneration patterns in myotonic dystrophy type I (DM1).
In two cohorts of DM1 patients, brain maps of volume loss (VL) and neuropsychological deficits (NDs) were intersected to large-scale transcriptome maps provided by the Allen Human Brain Atlas (AHBA). For validation, neuropathological and RNA analyses were performed in a small series of DM1 brain samples.
Twofold: (1) From a list of preselected hypothesis-driven genes, confirmatory analyses found that three genes play a major role in brain degeneration: dystrophin (DMD), alpha-synuclein (SNCA) and the microtubule-associated protein tau (MAPT). Neuropathological analyses confirmed a highly heterogeneous Tau-pathology in DM1, different to the one in Alzheimer's disease. (2) Exploratory analyses revealed gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. RNA analyses confirmed synaptic vesicle dysfunction.
The combination of large-scale transcriptome interactions with brain imaging and cognitive function sheds light on the neurobiological mechanisms of brain degeneration in DM1 that might help define future therapeutic strategies and research into this condition.
描绘 1 型肌强直性营养不良（DM1）中脑退化模式的神经遗传学特征。
在两个 DM1 患者队列中，将体积损失（VL）和神经心理学缺陷（NDs）的脑图与艾伦人类大脑图谱（AHBA）提供的大规模转录组图谱相交。为了验证，对一小系列 DM1 脑样本进行了神经病理学和 RNA 分析。
双重作用：（1）从一组预先选择的假设驱动基因列表中，验证分析发现三个基因在大脑退化中起主要作用：肌营养不良蛋白（DMD）、α-突触核蛋白（SNCA）和微管相关蛋白 tau（MAPT）。神经病理学分析证实了 DM1 中的 Tau 病理学高度异质，与阿尔茨海默病中的 Tau 病理学不同。（2）探索性分析揭示了富含中枢神经系统关键生物学过程的基因簇，如突触小泡再循环、定位、内吞作用和胞吐作用以及 5-羟色胺和多巴胺神经递质途径。RNA 分析证实了突触小泡功能障碍。
大规模转录组相互作用与脑成像和认知功能的结合揭示了 DM1 中脑退化的神经生物学机制，这可能有助于确定未来的治疗策略和对此病症的研究。
