多谷氨酰胺疾病的挑战:从功能失调的神经元回路到神经元特异性CAG重复不稳定性。

IF 4.9 2区 生物学
Roxana Deleanu
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引用次数: 0

摘要

一些影响人类神经系统的遗传疾病是无法治愈的,人们对它们的了解还不够充分。其中,聚谷氨酰胺(polyQ)家族有9种罕见疾病:亨廷顿病(HD)、脊髓小脑共济失调1、2、3、6、7、17型、齿状脑白球性萎缩症、脊髓和球性肌萎缩症。在大多数患者中,这些疾病进展数十年,导致严重的运动不协调和神经变性。尽管他们的串联重复延长遗传基因和编码的多q -含蛋白已被广泛研究,但神经元类型特异性病理及其症状前潜伏期尚待进一步研究。然而,最近在检测单核转录组以及HD死后大脑串联重复序列长度方面的进展,已经能够识别非常高的CAG重复序列大小,从而触发特定投射神经元的转录失调和细胞死亡。一个挑战是更好地理解运动协调回路的复杂性,包括基底神经节和小脑神经元,它们在每种疾病中最容易受到CAG高扩张的影响。另一个挑战是在单细胞分辨率下检测CAG重复长度的动态变化及其对脆弱神经元的影响。这将为识别脆弱的长投射神经元的病理事件和开发针对影响中枢神经系统投射神经元的所有串联重复扩张的靶向治疗提供一个平台。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Challenges in Polyglutamine Diseases: From Dysfunctional Neuronal Circuitries to Neuron-Specific CAG Repeat Instability.

Challenges in Polyglutamine Diseases: From Dysfunctional Neuronal Circuitries to Neuron-Specific CAG Repeat Instability.

Challenges in Polyglutamine Diseases: From Dysfunctional Neuronal Circuitries to Neuron-Specific CAG Repeat Instability.

Challenges in Polyglutamine Diseases: From Dysfunctional Neuronal Circuitries to Neuron-Specific CAG Repeat Instability.

Several genetic diseases affecting the human nervous system are incurable and insufficiently understood. Among them, nine rare diseases form the polyglutamine (polyQ) family: Huntington's disease (HD), spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy, and spinal and bulbar muscular atrophy. In most patients, these diseases progress over decades to cause severe movement incoordination and neurodegeneration. Although their inherited genes with tandem-repeat elongations and the encoded polyQ-containing proteins have been extensively studied, the neuronal-type-specific pathologies and their long pre-symptomatic latency await further investigations. However, recent advances in detecting the single-nucleus transcriptome, alongside the length of tandem repeats in HD post-mortem brains, have enabled the identification of very high CAG repeat sizes that trigger transcriptional dysregulation and cell death in specific projection neurons. One challenge is to better understand the complexity of movement coordination circuits, including the basal ganglia and cerebellum neurons, which are most vulnerable to the high CAG expansion in each disease. Another challenge is to detect dynamic changes in CAG repeat length and their effects in vulnerable neurons at single-cell resolution. This will offer a platform for identifying pathological events in vulnerable long projection neurons and developing targeted therapies for all tandem-repeat expansions affecting the CNS projection neurons.

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来源期刊
自引率
10.70%
发文量
13472
审稿时长
1.7 months
期刊介绍: The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).
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