Rare disease models provide insight into inherited forms of neurodegeneration.

Philippa C Fowler, Dwayne J Byrne, Niamh C O'Sullivan
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Abstract

Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been associated with HSP, however the majority of cases are caused by mutations that encode proteins responsible for generating and maintaining tubular endoplasmic reticulum (ER) structure. These ER-shaping proteins are vital for the long-term survival of axons, however the mechanisms by which mutations in these proteins give rise to HSP remain poorly understood. To begin to address this we have characterized in vivo loss of function models of two very rare forms of HSP caused by loss of the ER-shaping proteins ARL6IP1 (SPG61) and RTN2 (SPG12). These models display progressive locomotor defects, disrupted organisation of the tubular ER and length-dependant defects in the axonal mitochondrial network. Here we compare our findings with those associated with more common forms HSP including: Spastin, Atlastin-1 and REEP 1 which together account for over half of all cases of autosomal dominant HSP. Furthermore, we discuss recent observations in other HSP models which are directly implicated in mitochondrial function and localization. Overall, we highlight the common features of our rare models of HSP and other models of disease which could indicate shared mechanisms underpinning neurodegeneration in these disorders.

Abstract Image

罕见疾病模型让我们深入了解神经变性的遗传形式。
遗传性痉挛性截瘫(HSP)是一组遗传性神经退行性疾病,其特点是皮质脊髓束中最长的运动神经元逆行变性,导致下肢肌肉无力和痉挛。迄今为止,已有 70 多个基因位点与 HSP 有关,但大多数病例是由编码负责生成和维持管状内质网(ER)结构的蛋白质的突变引起的。这些内质网塑形蛋白对轴突的长期存活至关重要,但人们对这些蛋白的突变导致 HSP 的机制仍然知之甚少。为了着手解决这个问题,我们研究了两种非常罕见的 HSP 体内功能缺失模型,它们是由 ER 塑形蛋白 ARL6IP1(SPG61)和 RTN2(SPG12)的缺失引起的。这些模型表现出进行性运动缺陷、管状ER组织破坏以及轴突线粒体网络的长度依赖性缺陷。在此,我们将我们的研究结果与更常见的 HSP 形式进行了比较,包括Spastin、Atlastin-1 和 REEP 1,它们共占所有常染色体显性 HSP 病例的一半以上。此外,我们还讨论了最近在其他直接与线粒体功能和定位有关的 HSP 模型中的观察结果。总之,我们强调了罕见的 HSP 模型和其他疾病模型的共同特征,这些特征可能表明这些疾病神经变性的共同机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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