Ozyurt Tunch, Gautam Mukesh
Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Brain Sci. 2021 Jun 7;11(6):754. doi: 10.3390/brainsci11060754.
Corticospinal motor neurons (CSMN) are an indispensable neuron population for the motor neuron circuitry. They are excitatory projection neurons, which collect information from different regions of the brain and transmit it to spinal cord targets, initiating and controlling motor function. CSMN degeneration is pronounced cellular event in motor neurons diseases, such as amyotrophic lateral sclerosis (ALS). Genetic mutations contribute to only about ten percent of ALS. Thus understanding the involvement of other factors, such as epigenetic controls, is immensely valuable. Here, we investigated epigenomic signature of CSMN that become diseased due to misfolded SOD1 toxicity and TDP-43 pathology, by performing quantitative analysis of 5-methylcytosine (5mC) and 5-hydroxymethycytosine (5hmC) expression profiles during end-stage of the disease in hSOD1, and prpTDP-43 mice. Our analysis revealed that expression of 5mC was specifically reduced in CSMN of both hSOD1 and prpTDP-43 mice. However, 5hmC expression was increased in the CSMN that becomes diseased due to misfolded SOD1 and decreased in CSMN that degenerates due to TDP-43 pathology. These results suggest the presence of a distinct difference between different underlying causes. These differential epigenetic events might modulate the expression profiles of select genes, and ultimately contribute to the different paths that lead to CSMN vulnerability in ALS.
皮质脊髓运动神经元（CSMN）是运动神经元回路中不可或缺的神经元群体。它们是兴奋性投射神经元，从大脑的不同区域收集信息并将其传递到脊髓靶点，启动和控制运动功能。CSMN变性是运动神经元疾病（如肌萎缩侧索硬化症，ALS）中明显的细胞事件。基因突变仅导致约10%的ALS病例。因此，了解其他因素（如表观遗传调控）的作用具有极大的价值。在这里，我们通过对hSOD1和prpTDP - 43小鼠疾病末期的5 - 甲基胞嘧啶（5mC）和5 - 羟甲基胞嘧啶（5hmC）表达谱进行定量分析，研究了因错误折叠的SOD1毒性和TDP - 43病理而患病的CSMN的表观基因组特征。我们的分析表明，hSOD1和prpTDP - 43小鼠的CSMN中5mC的表达均特异性降低。然而，因错误折叠的SOD1而患病的CSMN中5hmC表达增加，而因TDP - 43病理而退化的CSMN中5hmC表达降低。这些结果表明不同潜在病因之间存在明显差异。这些不同的表观遗传事件可能会调节特定基因的表达谱，并最终导致导致ALS中CSMN易损性的不同途径。
