Algarve Biomedical Center-Research Institute, 8005-139 Faro, Portugal.
Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, 8005-139 Faro, Portugal.
Int J Mol Sci. 2022 Oct 7;23(19):11896. doi: 10.3390/ijms231911896.
Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal, dominantly inherited disease, in which the affected individuals have a disease onset around their third life decade. The molecular mechanisms underlying SCA2 are not yet completely understood, for which we hypothesize that aging plays a role in SCA2 molecular pathogenesis. In this study, we performed a striatal injection of mutant ataxin-2 mediated by lentiviral vectors, in young and aged animals. Twelve weeks post-injection, we analyzed the striatum for SCA2 neuropathological features and specific aging hallmarks. Our results show that aged animals had a higher number of mutant ataxin-2 aggregates and more neuronal marker loss, compared to young animals. Apoptosis markers, cleaved caspase-3, and cresyl violet staining also indicated increased neuronal death in the aged animal group. Additionally, mRNA levels of microtubule-associated protein 1 light-chain 3B (LC3) and sequestosome-1 (SQSTM1/p62) were altered in the aged animal group, suggesting autophagic pathway dysfunction. This work provides evidence that aged animals injected with expanded ataxin-2 had aggravated SCA2 disease phenotype, suggesting that aging plays an important role in SCA2 disease onset and disease progression.
脊髓小脑共济失调 2 型（SCA2）是一种罕见的常染色体显性遗传疾病，受影响的个体在其生命的第三个十年左右发病。SCA2 的分子机制尚不完全清楚，我们假设衰老在 SCA2 的分子发病机制中起作用。在这项研究中，我们通过慢病毒载体在年轻和年老的动物中进行纹状体注射突变型 ataxin-2。注射后 12 周，我们分析纹状体的 SCA2 神经病理学特征和特定的衰老标志物。我们的结果表明，与年轻动物相比，年老动物的突变型 ataxin-2 聚集体数量更多，神经元标志物丢失更多。凋亡标志物 cleaved caspase-3 和 cresyl violet 染色也表明衰老动物组的神经元死亡增加。此外，微管相关蛋白 1 轻链 3B（LC3）和自噬体相关蛋白 1（SQSTM1/p62）的 mRNA 水平在衰老动物组中发生改变，提示自噬途径功能障碍。这项工作提供了证据表明，用扩增的 ataxin-2 注射的老年动物具有加重的 SCA2 疾病表型，这表明衰老在 SCA2 的发病和疾病进展中起着重要作用。
