Systemic manifestation and contribution of peripheral tissues to Huntington's disease pathogenesis.
Systemic manifestation and contribution of peripheral tissues to Huntington's disease pathogenesis.
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DOI：
10.1016/j.arr.2021.101358
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发表时间：
2021-08
影响因子：
13.1
通讯作者：
Demontis F
中科院分区：
文献类型：
--
作者：
Chuang CL;Demontis F
亨廷顿病（HD）是由亨廷顿（HTT）基因中的胞嘧啶/腺苷/鸟嘌呤重复序列扩增引起的常染色体显性神经变性疾病，其导致毒性的、易于聚集的突变HTT-polyQ蛋白。除了在中枢神经系统中确立的HD进展机制之外，越来越多的证据表明，外周组织也受到HD的影响，并且源自外周组织的全身信号传导可以影响脑中HD的进展。在此，我们回顾了HD在外周组织中的系统表现，以及系统信号对HD发病机制的影响。突变HTT主要通过其在骨骼肌、骨、脂肪组织和心脏中的活性诱导身体消耗综合征（恶病质）。由突变HTT诱导的其他整体生物体效应包括全身代谢稳态的下降，其源于胰腺、肝脏、肠道、下丘脑-垂体-肾上腺轴和昼夜节律功能的紊乱。除了通过血流和渗漏的血脑屏障传播外，HTT-polyQ还可以通过神经元的吸收以及从外周神经系统到中枢神经系统的轴突运输进行长距离传播。最后，响应于治疗干预（例如运动）或响应于外周组织中的突变HTT活性而产生和/或分泌的信号传导因子可能影响HD。总之，这些研究表明HD是一种全身性疾病，受组织间信号传导和外周组织中致病性HTT作用的影响。我们建议HD的治疗策略应包括改善外周组织中的HD症状。此外，利用外周组织和大脑之间的信号传导可以提供用于减少中枢神经系统中的HD进展的手段。
Huntington disease (HD) is an autosomal dominant neurodegenerative disease that is caused by expansion of cytosine/adenosine/guanine repeats in the huntingtin (HTT) gene, which leads to a toxic, aggregation-prone, mutant HTT-polyQ protein. Beyond the well-established mechanisms of HD progression in the central nervous system, growing evidence indicates that also peripheral tissues are affected in HD and that systemic signaling originating from peripheral tissues can influence the progression of HD in the brain. Herein, we review the systemic manifestation of HD in peripheral tissues, and the impact of systemic signaling on HD pathogenesis. Mutant HTT induces a body wasting syndrome (cachexia) primarily via its activity in skeletal muscle, bone, adipose tissue, and heart. Additional whole-organism effects induced by mutant HTT include decline in systemic metabolic homeostasis, which stems from derangement of pancreas, liver, gut, hypothalamic–pituitary–adrenal axis, and circadian functions. In addition to spreading via the bloodstream and a leaky blood brain barrier, HTT-polyQ may travel long distance via its uptake by neurons and its axonal transport from the peripheral to the central nervous system. Lastly, signaling factors that are produced and/or secreted in response to therapeutic interventions such as exercise or in response to mutant HTT activity in peripheral tissues may impact HD. In summary, these studies indicate that HD is a systemic disease that is influenced by intertissue signaling and by the action of pathogenic HTT in peripheral tissues. We propose that treatment strategies for HD should include the amelioration of HD symptoms in peripheral tissues. Moreover, harnessing signaling between peripheral tissues and the brain may provide a means for reducing HD progression in the central nervous system.
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