Distinct multilevel misregulations of Parkin and PINK1 revealed in cell and animal models of TDP-43 proteinopathy.

Parkin and PINK1 play an important role in mitochondrial quality control, whose malfunction may also be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Excessive TDP-43 accumulation is a pathological hallmark of ALS and is associated with Parkin protein reduction in spinal cord neurons from sporadic ALS patients. In this study, we reveal that Parkin and PINK1 are differentially misregulated in TDP-43 proteinopathy at RNA and protein levels. Using knock-in flies, mouse primary neurons, and TDP-43Q331K transgenic mice, we further unveil that TDP-43 downregulates Parkin mRNA, which involves an unidentified, intron-independent mechanism and requires the RNA-binding and the protein–protein interaction functions of TDP-43. Unlike Parkin, TDP-43 does not regulate PINK1 at an RNA level. Instead, excess of TDP-43 causes cytosolic accumulation of cleaved PINK1 due to impaired proteasomal activity, leading to compromised mitochondrial functions. Consistent with the alterations at the molecular and cellular levels, we show that transgenic upregulation of Parkin but downregulation of PINK1 suppresses TDP-43-induced degenerative phenotypes in a Drosophila model of ALS. Together, these findings highlight the challenge associated with the heterogeneity and complexity of ALS pathogenesis, while pointing to Parkin–PINK1 as a common pathway that may be differentially misregulated in TDP-43 proteinopathy.

帕金（Parkin）和PINK1在线粒体质量控制中起重要作用，其功能失调可能也参与肌萎缩侧索硬化（ALS）的发病机制。TDP - 43过度积累是ALS的一个病理特征，并且与散发性ALS患者脊髓神经元中帕金蛋白的减少有关。在这项研究中，我们揭示在TDP - 43蛋白病中，帕金和PINK1在RNA和蛋白质水平上受到不同的异常调节。利用基因敲入果蝇、小鼠原代神经元以及TDP - 43Q331K转基因小鼠，我们进一步揭示TDP - 43下调帕金mRNA，这涉及一种未知的、不依赖内含子的机制，并且需要TDP - 43的RNA结合以及蛋白质 - 蛋白质相互作用功能。与帕金不同，TDP - 43在RNA水平上不调节PINK1。相反，由于蛋白酶体活性受损，过量的TDP - 43导致切割后的PINK1在细胞质中积累，从而导致线粒体功能受损。与分子和细胞水平的改变相一致，我们表明在一个ALS果蝇模型中，帕金的转基因上调以及PINK1的下调抑制了TDP - 43诱导的退行性表型。总之，这些发现凸显了与ALS发病机制的异质性和复杂性相关的挑战，同时指出帕金 - PINK1是一个在TDP - 43蛋白病中可能受到不同异常调节的共同通路。