TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response

by Peng Wang, Jianwen Deng, Jie Dong, Jianghong Liu, Eileen H. Bigio, Marsel Mesulam, Tao Wang, Lei Sun, Li Wang, Alan Yueh-Luen Lee, Warren A. McGee, Xiaoping Chen, Kazuo Fushimi, Li Zhu, Jane Y. Wu Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain uncl ear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultr astructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TD P-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our ...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research

Related Links:

CONCLUSIONS: The varied pharmacologic mechanisms of NBP involve many complex molecular mechanisms; however, there many unknown pharmacologic effects await further study. PMID: 31205106 [PubMed - in process]
Source: Chinese Medical Journal - Category: General Medicine Authors: Tags: Chin Med J (Engl) Source Type: research
This study provides novel insight into genetic determinants of poor outcomes after acute injury to the neonatal brain and how early-life brain injury can influence adult-onset neurodegenerative disease during aging.
Source: Frontiers in Neurology - Category: Neurology Source Type: research
Abstract Protein folding is the process by which a polypeptide chain acquires its functional, native 3D structure. Protein misfolding, on the other hand, is a process in which proteins fails to fold into its native functional conformation. This misfolding of proteins may lead to precipitation of number of serious diseases such as Cystic fibrosis (CF), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) etc. Protein quality-control (PQC) systems, consisting of molecular chaperones, proteases and regulatory factors, help in protein folding and prevent its aggregation. At the s...
Source: Current Protein and Peptide Science - Category: Biochemistry Authors: Tags: Curr Protein Pept Sci Source Type: research
Publication date: Available online 4 June 2019Source: Seminars in Cell &Developmental BiologyAuthor(s): Nicol Birsa, Matthew Peter Bentham, Pietro FrattaAbstractTAR DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS) are RNA binding proteins (RBPs) primarily located in the nucleus, and involved in numerous aspects of RNA metabolism. Both proteins can be found to be depleted from the nucleus and accumulated in cytoplasmic inclusions in two major neurodegenerative conditions, amyotrophic lateral sclerosis and frontotemporal dementia. Recent evidences suggest that, in addition to their nuclear functions, b...
Source: Seminars in Cell and Developmental Biology - Category: Cytology Source Type: research
Publication date: Available online 31 May 2019Source: NeuroscienceAuthor(s): Zoë P. Van Acker, Ken Declerck, Evi Luyckx, Wim Vanden Berghe, Sylvia DewildeAbstractNeuroglobin (Ngb) is a REST/NRSF-regulated protein, active in reactive oxygen species detoxification and cytochrome c inhibition, which provides a beneficial outcome in pathologies as Alzheimer's disease and strokes. Considering that oxidative stress and cell death are typical hallmarks of amyotrophic lateral sclerosis (ALS), we sought to explore Ngb's involvement along this disease progression. Ngb transcription was detected to be 2-fold down-regulated in la...
Source: Neuroscience - Category: Neuroscience Source Type: research
CONCLUSIONS: The varied pharmacological mechanisms of NBP involve many complex molecular mechanisms; however, there many unknown pharmacological effects await further study.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID: 31107716 [PubMed - as supplied by publisher]
Source: Chinese Medical Journal - Category: General Medicine Authors: Tags: Chin Med J (Engl) Source Type: research
In this study, a significant (30%) increase in maximum lifespan of mice was found after nonablative transplantation of 100 million nucleated bone marrow (BM) cells from young donors, initiated at the age that is equivalent to 75 years for humans. Moreover, rejuvenation was accompanied by a high degree of BM chimerism for the nonablative approach. Six months after the transplantation, 28% of recipients' BM cells were of donor origin. The relatively high chimerism efficiency that we found is most likely due to the advanced age of our recipients having a depleted BM pool. In addition to the higher incorporation rates, ...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
This article is protected by copyright. All rights reserved. PMID: 31074054 [PubMed - as supplied by publisher]
Source: The Journal of Physiology - Category: Physiology Authors: Tags: J Physiol Source Type: research
Conclusions: This study demonstrated that NAR targeted microglial NLRP3 inflammasome to protect DA neurons against LPS-induced neurotoxicity. These findings suggest NAR might hold a promising therapeutic potential for PD. Background Parkinson's disease (PD) is the second most prevalent central nervous system (CNS) degenerative disease. It is characterized by slow and progressive loss of dopamine (DA) neurons in the midbrain substantia nigra (SN) with the accumulation of α-synuclein in Lewy bodies and neuritis (1). Although the etiology of PD remains unclear, amounts of studies have suggested that neur...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Albert Sanfeliu1, Karsten Hokamp2, Michael Gill1 and Daniela Tropea1,3*1Neuropsychiatric Genetics, Department of Psychiatry, School of Medicine, Trinity Translational Medicine Institute, St James Hospital, Dublin, Ireland2Department of Genetics, School of Genetics and Microbiology, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland3Department of Psychiatry, School of Medicine, Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, IrelandRett syndrome is a rare neuropsychiatric disorder with a wide symptomatology including impaired communication and movement, cardio-respiratory abno...
Source: Frontiers in Psychiatry - Category: Psychiatry Source Type: research
More News: ALS | Brain | Genetics | Mitochondrial Disease | Neurology | Study