p62 过表达导致 TDP-43 细胞质定位错误、聚集和切割以及神经元死亡。

p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death.

机构信息

Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.

Harry Perkins Institute of Medical Research, University of Western Australia, Crawley, WA, Australia.

出版信息

Sci Rep. 2021 Jun 1;11(1):11474. doi: 10.1038/s41598-021-90822-2.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) that exist on a spectrum of neurodegenerative disease. A hallmark of pathology is cytoplasmic TDP-43 aggregates within neurons, observed in 97% of ALS cases and ~ 50% of FTLD cases. This mislocalisation from the nucleus into the cytoplasm and TDP-43 cleavage are associated with pathology, however, the drivers of these changes are unknown. p62 is invariably also present within these aggregates. We show that p62 overexpression causes TDP-43 mislocalisation into cytoplasmic aggregates, and aberrant TDP-43 cleavage that was dependent on both the PB1 and ubiquitin-associated (UBA) domains of p62. We further show that p62 overexpression induces neuron death. We found that stressors (proteasome inhibition and arsenic) increased p62 expression and that this shifted the nuclear:cytoplasmic TDP-43 ratio. Overall, our study suggests that environmental factors that increase p62 may thereby contribute to TDP-43 pathology in ALS and FTLD.

肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）存在于神经退行性疾病的谱系中。病理学的一个标志是神经元内细胞质 TDP-43 聚集，在 97%的 ALS 病例和~50%的 FTLD 病例中观察到。这种从核内到细胞质的定位改变和 TDP-43 切割与病理学有关，然而，这些变化的驱动因素尚不清楚。p62 也总是存在于这些聚集体中。我们表明，p62 的过表达导致 TDP-43 向细胞质聚集体的定位改变，并导致 TDP-43 异常切割，这依赖于 p62 的 PB1 和泛素结合（UBA）结构域。我们进一步表明，p62 的过表达诱导神经元死亡。我们发现应激源（蛋白酶体抑制和砷）增加了 p62 的表达，从而改变了核质 TDP-43 的比例。总的来说，我们的研究表明，增加 p62 的环境因素可能导致 ALS 和 FTLD 中 TDP-43 病理学的发生。