The degeneration of motoneurons is a common pathological hallmark of spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). While ALS affects upper motoneurons in the cerebral cortex and the brainstem as well as lower motoneurons in the ventral horn of the spinal cord, SMA is characterized by lower motoneuron pathology only. In ALS, symptoms typically develop in advanced adulthood leading to death within months to years after onset, mainly by respiratory failure (Salameh and others 2015). The clinical phenotypes include lower motoneuron symptoms such as fasciculation and muscular atrophy or upper motoneuron symptoms like spasticity and increased reflexes (Salameh and others 2015). Different subtypes are discriminated dependent on the earliest observable symptoms: bulbar onset represents a minor fraction of the cases while two thirds of patients display limb onset (Salameh and others 2015). In SMA, five clinical subtypes can be discriminated dependent on disease onset, survival, and ability of patients reaching certain motor function milestones (Wang and others 2007; Zerres and Rudnik-Schoneborn 1995). The most severe SMA type 0, the congenital SMA, has a prenatal onset and is lethal within the first month after birth (Grotto and others 2016). The most common SMA type, severe SMA type I, is one of the main genetic causes for infant death and patients never reach the ability of sitting without help (Finkel and others 2014). Patients suffering from intermediate SMA type II are able to sit but never accomplish walking and most patients reach adulthood (Kaufmann and others 2012). In juvenile SMA type III, patients with muscle weakness reach the ability of walking with a normal life expectancy (Piepers and others 2008). Although clinical symptoms are similar for ALS and SMA, the etiologies of diseases largely differ from each other. SMA is a monogenic disease while 90% of ALS cases are sporadic (SALS) and only 10% are hereditary with several genes involved (FALS) (Renton and others 2014). SMA is caused by mutations or deletion of the Survival of Motoneuron 1 (SMN1) gene (Lefebvre and others 1995). Severity of the disease is modified by a second gene, SMN2. Although coding for the same protein, SMN2 differs from SMN1 in several base pair exchanges (Lorson and others 1999). One of those exchanges, a C to T transition within exon 7, is located within an exonic splice enhancer region resulting in only partially spliced SMN mRNA. As a consequence, low levels of functional full-length SMN protein originate from the SMN2 gene (Lorson and Androphy 2000) only partially rescuing a loss of SMN1 in SMA patients. Consistently, the SMN2 copy number inversely correlates with SMA disease severity. Thus, SMA is caused by functional loss of the SMN protein either by low protein levels or by mutated SMN. FALS is mainly inherited in an autosomal dominant manner but there are also autosomal recessive or X-chromosomal-linked heredities (Renton and others 2014). The main gene alterations with high penetrance are chromosome 9 open reading frame 72 (C9orf72) repeat expansions, or mutations of superoxide dismutase 1 (SOD1), FUS RNA binding protein (FUS), and TAR DNA binding protein (TARDP, TDP-43) (Lattante and others 2015). Together with other more rarely affected genes they form a group of about 20 genes that cause ALS (Marangi and Traynor 2015). Moreover, genes and their variants have been identified that do not necessarily lead to ALS but are associated with the disease (van Rheenen and others 2016). Together with high-risk genes they form a group of about 100 genes linked with ALS pathology.

中文翻译：

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SMA和ALS中的肌动蛋白细胞骨架：它如何导致Mouranturon变性？

运动神经元的变性是脊髓性肌萎缩症（SMA）和肌萎缩性侧索硬化症（ALS）的常见病理标志。ALS影响大脑皮质和脑干中的上运动神经元以及脊髓腹角中的下运动神经元，而SMA仅表现为下运动神经元病理。在ALS中，症状通常在成年晚期发展，导致发病后数月至数年内死亡，主要是由于呼吸衰竭（Salameh等人，2015）。临床表型包括较低的运动神经元症状（如束缚和肌肉萎缩）或较高的运动神经元症状（如痉挛和反射增加）（Salameh等人，2015）。根据最早可观察到的症状区分不同的亚型：延髓起病仅占病例的一小部分，而三分之二的患者表现出肢体起病（Salameh等人，2015）。在SMA中，可以根据疾病发作，生存和达到某些运动功能里程碑的患者的能力来区分五种临床亚型（Wang等人2007； Zerres和Rudnik-Schoneborn 1995）。最严重的0型SMA是先天性SMA，具有产前发作，在出生后的第一个月内具有致死性（Grotto等人2016）。最常见的SMA类型是I型严重SMA，是婴儿死亡的主要遗传原因之一，患者无法在没有帮助的情况下就无法坐下（Finkel等人，2014）。患有II型中度SMA的患者能够坐下来，但永远无法完成行走，并且大多数患者已成年（Kaufmann等人，2012）。在III型SMA青少年中，肌肉无力的患者达到正常预期寿命的步行能力（Piepers等人，2008年）。尽管ALS和SMA的临床症状相似，但疾病的病因却彼此大相径庭。SMA是一种单基因疾病，而90％的ALS病例是散发性（SALS），只有10％是遗传性的，涉及多个基因（FALS）（Renton等，2014）。SMA是由Motoneuron 1（SMN1）基因的存活突变或缺失引起的（Lefebvre等，1995）。该疾病的严重程度由第二个基因SMN2修饰。尽管编码相同的蛋白质，SMN2在几个碱基对交换中与SMN1不同（Lorson等1999）。这些交换之一是外显子7内的C到T转换，位于外显子剪接增强子区域内，仅导致部分剪接的SMN mRNA。作为结果，低水平的功能性全长SMN蛋白源自SMN2基因（Lorson和Androphy 2000），仅部分挽救了SMA患者的SMN1丢失。一致地，SMN2拷贝数与SMA疾病严重程度成反比。因此，SMA是由低蛋白水平或突变的SMN引起的SMN蛋白功能丧失引起的。FALS主要以常染色体显性方式遗传，但也存在常染色体隐性遗传或X染色体连锁遗传（Renton等人，2014）。高渗透率的主要基因改变是9号染色体开放阅读框72（C9orf72）重复扩增，或超氧化物歧化酶1（SOD1），FUS RNA结合蛋白（FUS）和TAR DNA结合蛋白（TARDP，TDP-43）的突变。 （Lattante等人，2015年）。它们与其他很少受影响的基因一起，构成导致ALS的约20个基因的组（Marangi和Traynor，2015年）。此外，已鉴定出不一定导致ALS但与疾病相关的基因及其变体（van Rheenen等，2016）。它们与高风险基因一起形成了约100个与ALS病理相关的基因。