Bergonzoni Guendalina, Döring Jessica, Biagioli Marta
NeuroEpigenetics Laboratory, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
Front Cell Neurosci. 2021 Feb 10;15:628010. doi: 10.3389/fncel.2021.628010. eCollection 2021.
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an aberrant expansion of the CAG tract within the exon 1 of the gene, . HD progressively impairs motor and cognitive capabilities, leading to a total loss of autonomy and ultimate death. Currently, no cure or effective treatment is available to halt the disease. Although the gene is ubiquitously expressed, the striatum appears to be the most susceptible district to the HD mutation with Medium-sized Spiny Neurons (MSNs) (D1R and D2R) representing 95% of the striatal neuronal population. Why are striatal MSNs so vulnerable to the HD mutation? Particularly, why do D1R- and D2R-MSNs display different susceptibility to HD? Here, we highlight significant differences between D1R- and D2R-MSNs subpopulations, such as morphology, electrophysiology, transcriptomic, functionality, and localization in the striatum. We discuss possible reasons for their selective degeneration in the context of HD. Our review suggests that a better understanding of cell type-specific gene expression dysregulation within the striatum might reveal new paths to therapeutic intervention or prevention to ameliorate HD patients' life expectancy.
亨廷顿舞蹈症（HD）是一种毁灭性的神经退行性疾病，由该基因第1外显子内CAG序列的异常扩增引起。HD会逐渐损害运动和认知能力，导致完全丧失自主能力并最终死亡。目前，尚无治愈方法或有效治疗手段来阻止该疾病。尽管该基因在全身广泛表达，但纹状体似乎是对HD突变最敏感的区域，其中中型多棘神经元（MSNs）（D1R和D2R）占纹状体神经元总数的95%。为什么纹状体MSNs对HD突变如此脆弱？特别是，为什么D1R-MSNs和D2R-MSNs对HD表现出不同的易感性？在这里，我们强调了D1R-MSNs和D2R-MSNs亚群之间的显著差异，如形态学、电生理学、转录组学、功能以及在纹状体中的定位。我们讨论了在HD背景下它们选择性退化的可能原因。我们的综述表明，更好地理解纹状体内细胞类型特异性基因表达失调可能会揭示改善HD患者预期寿命的治疗干预或预防的新途径。
