近日，美国哈佛大学Steven A. McCarroll等研究人员合作发现，长片段体细胞DNA重复扩展驱动亨廷顿病中的神经退行性变。相关论文于2025年1月16日在线发表于国际学术期刊《细胞》。

研究人员表示，在亨廷顿病（HD）中，纹状体投射神经元（SPN）在中年期间退化；核心生物学问题是导致神经退行性变的致病DNA重复序列（CAG）_n如何在数十年的生物学潜伏期后引发退行性变化。

研究人员开发了一种单细胞方法，用于测量这一重复序列的长度以及全基因组RNA表达。研究人员发现，HTT CAG重复序列在SPN中从40-45扩展到100-500+ CAG。40到150 CAG的体细胞扩展没有明显的细胞自主效应，但拥有150-500+ CAG的SPN失去了神经元身份的正面特征，然后是负面特征，去抑制了衰老/凋亡基因，最终这些细胞丧失。

这些结果表明，超过150 CAG的体细胞重复扩展导致SPN快速且不同步地退化。研究人员得出结论，在HD中，在任何时刻，大多数神经元都拥有无害但不稳定的HTT基因，而HD的发病机制是几乎贯穿神经元一生的DNA过程。

附：英文原文

Title: Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease

Author: Robert E. Handsaker, Seva Kashin, Nora M. Reed, Steven Tan, Won-Seok Lee, Tara M. McDonald, Kiely Morris, Nolan Kamitaki, Christopher D. Mullally, Neda R. Morakabati, Melissa Goldman, Gabriel Lind, Rhea Kohli, Elisabeth Lawton, Marina Hogan, Kiku Ichihara, Sabina Berretta, Steven A. McCarroll

Issue&Volume: 2025-01-16

Abstract: In Huntington’s disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG)n in the huntingtin (HTT) gene leads to neurodegeneration after decades of biological latency. We developed a single-cell method for measuring this repeat’s length alongside genome-wide RNA expression. We found that the HTT CAG repeat expands somatically from 40–45 to 100–500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150–500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost. Our results suggest that somatic repeat expansion beyond 150 CAGs causes SPNs to degenerate quickly and asynchronously. We conclude that in HD, at any one time, most neurons have an innocuous but unstable HTT gene and that HD pathogenesis is a DNA process for almost all of a neuron’s life.

DOI: 10.1016/j.cell.2024.11.038

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01379-5