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

Xing Sun,Caixia Qin,Ang Li,Gang Duan,Ke Xiang,Yongjia Duan,Xu Cao,Jian-Chiuan Li,Chun-Hong Chen,Kuili Tian,Xue Deng,Yanshan Fang,Jiangxia Ni

doi:10.1038/s41419-018-1022-y

Abstract

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive motor neuron loss, leading to muscle weakness and wasting
We examined the mRNA levels of Parkin and PINK1 in human 293T cells transfected with human TDP-43 (hTDP-43)-HA and mouse primary neurons infected with lentivirus to express hTDP-43-HA (Fig. S1A)
Parkin mRNA levels were decreased in the brain of TDP43 KD mice; whereas in sALS patient cells, Parkin protein level decrease was associated with excessive TDP-43 accumulation[12]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive motor neuron loss, leading to muscle weakness and wasting. ALS is incurable and the patients usually die within 2–5 years after diagnosis. The majority (>90%) of ALS cases are sporadic (sALS) with unknown causes, whereas mutations in genes such as SOD1, C9orf[72], FUS, and TARDBP are reported to cause familial ALS that accounts for the remaining 10%1,2. TDP-43 protein is predominantly localized to the nucleus. It belongs to the heterogeneous ribonucleoprotein family and plays an important role in regulating gene transcription, RNA processing, transport, and stability, as well as the formation of stress granules. In disease conditions, ubiquitinated TDP-43 accumulates in the cytoplasm.

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Conclusion