Neuroscience Research Australia, Sydney, Australia.
School of Medical Sciences, University of New South Wales, Sydney, Australia.
Ann Neurol. 2016 Feb;79(2):295-305. doi: 10.1002/ana.24565. Epub 2016 Jan 14.
Despite evidence suggesting that the cerebellum may be targeted in amyotrophic lateral sclerosis (ALS), particularly in cases with repeat expansions in the ATXN2 and C9ORF72 genes, the integrity of cerebellar neurons has yet to be examined. The present study undertakes a histopathological analysis to assess the impact of these repeat expansions on cerebellar neurons and determine whether similar cerebellar pathology occurs in sporadic disease.
Purkinje and granule cells were quantified in the vermis and lateral cerebellar hemispheres of ALS cases with repeat expansions in the ATXN2 and C9ORF72 genes, sporadic disease, and sporadic progressive muscular atrophy with only lower motor neuron degeneration.
ALS cases with intermediate repeat expansions in the ATXN2 gene demonstrate a significant loss in Purkinje cells in the cerebellar vermis only. Despite ALS cases with expansions in the C9ORF72 gene having the highest burden of inclusion pathology, no neuronal loss was observed in this group. Neuronal numbers were also unchanged in sporadic ALS and sporadic PMA cases.
The present study has established a selective loss of Purkinje cells in the cerebellar vermis of ALS cases with intermediate repeat expansions in the ATXN2 gene, suggesting a divergent pathogenic mechanism independent of upper and lower motor neuron degeneration in ALS. We discuss these findings in the context of large repeat expansions in ATXN2 and spinocerebellar ataxia type 2, providing evidence that intermediate repeats in ATXN2 cause significant, albeit less substantial, spinocerebellar damage compared with longer repeats in ATXN2.
尽管有证据表明小脑可能是肌萎缩侧索硬化症（ALS）的靶点，特别是在 ATXN2 和 C9ORF72 基因重复扩展的情况下，但小脑神经元的完整性尚未得到检查。本研究进行了组织病理学分析，以评估这些重复扩展对小脑神经元的影响，并确定是否在散发性疾病中发生类似的小脑病变。
在 ATXN2 和 C9ORF72 基因重复扩展的 ALS 病例、散发性疾病和仅有下运动神经元退变的散发性进行性肌萎缩症中，对小脑蚓部和外侧小脑半球的浦肯野和颗粒细胞进行了量化。
ATXN2 基因中间重复扩展的 ALS 病例仅在小脑蚓部显示浦肯野细胞明显丢失。尽管 C9ORF72 基因扩展的 ALS 病例具有最高的包涵体病理负担，但在该组中未观察到神经元丢失。在散发性 ALS 和散发性 PMA 病例中，神经元数量也没有变化。
本研究确立了 ATXN2 基因中间重复扩展的 ALS 病例中小脑蚓部浦肯野细胞的选择性丢失，表明与 ALS 中上下运动神经元退变无关的不同致病机制。我们在 ATXN2 中的大重复扩展和脊髓小脑性共济失调 2 型的背景下讨论了这些发现，提供了证据表明 ATXN2 中的中间重复导致明显但不那么实质性的脊髓小脑损伤，与 ATXN2 中的较长重复相比。
