Autophagy and Ubiquitin-Proteasome System Coordinate to Regulate the Protein Quality Control of Neurodegenerative Disease-Associated DCTN1.

Abstract

Motor neuron diseases are neurodegenerative diseases that are characterized by degeneration of the upper and lower motor neurons in the central nervous system. Mutations in Dynactin 1 (DCTN1), a component in the Dynein/Dynactin motor complex, have been previously identified to cause motor neuron diseases and other neurodegenerative disorders. Recent studies showed that motor neuron disease-linked mutation, such as G59S mutation, could lead to dysfunction and protein aggregation of DCTN1. However, the cellular pathway involved in the clearance of DCTN1 aggregates is still not fully elucidated. In this study, we employed a culture cell model of DCTN1-linked neurodegeneration and explored the role of cellular protein control systems in the regulation of wild type and mutant DCTN1. We find that the ubiquitin-proteasome system, but not autophagy, is the primary protein degradation system for the turnover of both wild type and G59S DCTN1 under normal conditions. However, it turns out that autophagy can play a role in the clearance of protein aggregates of G59S DCTN1 when the proteasome activity is inhibited. Importantly, overexpression of TFEB, a master regulator of autophagy, promotes the autophagic clearance of G59S DCTN1 aggregates and ameliorates G59S DCTN1-induced cytotoxicity when the proteasomes are impaired. In conclusion, autophagy may play as a backup system to protect cells against the cytotoxicity induced by aggregate-prone DCTN1 when proteasomal function is damaged.

• Authors: Nana Wang, Qilian Ma, Panpan Peng, Yunhao Yu, Shiqiang Xu, Guanghui Wang, Zheng Ying, Hongfeng Wang
• Journal: Neurotoxicity research (Neurotox Res) Vol. 37 Issue 1 Pg. 48-57 (Jan 2020) ISSN: 1476-3524 [Electronic] United States
• PMID: 31654383 (Publication Type: Journal Article)

Chemical References

• DCTN1 protein, human
• Dynactin Complex
• Ubiquitin
• Proteasome Endopeptidase Complex

Topics

• Animals
• Autophagy (physiology)
• Cell Survival
• Cells, Cultured
• Dynactin Complex (genetics, physiology)
• Humans
• Mice
• Microtubules (metabolism)
• Mutation
• Neurodegenerative Diseases (physiopathology)
• Plasmids
• Proteasome Endopeptidase Complex (physiology)
• Protein Aggregation, Pathological (genetics, metabolism)
• Proteolysis
• Transfection
• Ubiquitin (physiology)