Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA, 19107, USA.
Laboratory Animal Center, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, 030012, People's Republic of China.
Acta Neuropathol Commun. 2018 Nov 8;6(1):122. doi: 10.1186/s40478-018-0627-9.
Mutations in ubiquilin2 (UBQLN2) have been linked to abnormal protein aggregation in amyotrophic lateral sclerosis (ALS). The mechanisms underlying UBQLN2-related neurodegenerative diseases remain unclear. Using a tetracycline-regulated gene expression system, the ALS-linked UBQLN2 mutant was selectively expressed in either the spinal motor neurons or astrocytes in rats. We found that selectively expressing mutant UBQLN2 in the spinal motor neurons caused several core features of ALS, including the progressive degeneration of motor neurons, the denervation atrophy of skeletal muscles, and the abnormal protein accumulation. Furthermore, mutant UBQLN2 accumulation was associated with an age-dependent decrease in several core autophagy-related proteins. ALS-like phenotypes were not observed when mutant UBQLN2 was overexpressed in the astrocytes, however, even though the expression of the mutant UBQLN2 protein was higher in these rats. Our results suggest that selectively expressing mutant UBQLN2 in motor neurons is sufficient to trigger the development of ALS in rats. Our results further indicate that the compromised autophagy-lysosomal pathway plays a critical role in the pathogenesis of UBQLN2-related neurodegenerative diseases.
泛素结合酶 2（UBQLN2）中的突变与肌萎缩侧索硬化症（ALS）中的异常蛋白聚集有关。UBQLN2 相关神经退行性疾病的发病机制仍不清楚。本研究使用四环素调控的基因表达系统，在大鼠的脊髓运动神经元或星形胶质细胞中选择性表达 ALS 相关的 UBQLN2 突变体。我们发现，选择性地在脊髓运动神经元中表达突变型 UBQLN2 会导致多种 ALS 的核心特征，包括运动神经元的进行性退化、骨骼肌的去神经萎缩以及异常蛋白的积累。此外，突变型 UBQLN2 的积累与几种核心自噬相关蛋白的年龄依赖性下降有关。然而，当突变型 UBQLN2 在星形胶质细胞中过度表达时，并未观察到类似 ALS 的表型，尽管这些大鼠中突变型 UBQLN2 蛋白的表达水平更高。我们的研究结果表明，选择性地在运动神经元中表达突变型 UBQLN2 足以在大鼠中引发 ALS 的发生。我们的结果进一步表明，受损的自噬溶酶体途径在 UBQLN2 相关神经退行性疾病的发病机制中起着关键作用。
