Mechanisms of TDP-43 Proteinopathy Onset and Propagation

Abstract

TDP-43 is an RNA-binding protein that has been robustly linked to the pathogenesis of a number of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia. While mutations in the TARDBP gene that codes for the protein have been identified as causing disease in a small subset of patients, TDP-43 proteinopathy is present in the majority of cases regardless of mutation status. This raises key questions regarding the mechanisms by which TDP-43 proteinopathy arises and spreads throughout the central nervous system. Numerous studies have explored the role of a variety of cellular functions on the disease process, and nucleocytoplasmic transport, protein homeostasis, RNA interactions and cellular stress have all risen to the forefront as possible contributors to the initiation of TDP-43 pathogenesis. There is also a small but growing body of evidence suggesting that aggregation-prone TDP-43 can recruit physiological TDP-43, and be transmitted intercellularly, providing a mechanism whereby small-scale proteinopathy spreads from cell to cell, reflecting the spread of clinical symptoms observed in patients. This review will discuss the potential role of the aforementioned cellular functions in TDP-43 pathogenesis, and explore how aberrant pathology may spread, and result in a feed-forward cascade effect, leading to robust TDP-43 proteinopathy and disease.

The Protective Effect of Edaravone on TDP-43 Plus Oxidative Stress-Induced Neurotoxicity in Neuronal Cells: Analysis of Its Neuroprotective Mechanisms Using RNA Sequencing

“…In 1464R neuronal cells, TDP-43 and oxidative stress induced the expression of genes related to multiple pathways, including Nrf2, UPR, and autophagy, consistent with previous reports on TDP-43 proteinopathy and ALS [ 63 , 64 , 65 ]. These changes may contribute to adaptive responses of neuronal cells to oxidative stress and ER stress.…”

Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice

“…TDP-43 is another protein that has been robustly linked to the pathogenesis of several neurodegenerative disorders [ 37 ]. More than 90% of patients with sporadic amyotrophic lateral sclerosis and about 50% of frontotemporal lobar degeneration (FTLD) patients exhibit widespread abnormality of TDP-43 [ 38 , 39 ].…”

MRI biomarkers and neuropsychological assessments of hippocampal and parahippocampal regions affected by ALS: A systematic review

“…According to recent research, the loss‐of‐function impact of C9orf72, combined with certain gain‐of‐function entities, is required to develop a severe FTD/ALS phenotype 85 . TDP‐43 is a protein involved in RNA metabolism linked to the development of ALS and FTD 86 . Alzheimer's disease can occasionally result in neuronal death and gliosis in the hippocampus, a kind of TDP‐43 pathology known as hippocampal sclerosis 87 .…”

“…85 TDP-43 is a protein involved in RNA metabolism linked to the development of ALS and FTD. 86 Alzheimer's disease can occasionally result in neuronal death and gliosis in the hippocampus, a kind of TDP-43 pathology known as hippocampal sclerosis. 87 According to research, limbic-predominant age-related TDP-43 encephalopathy (LATE) is associated with a progressive amnestic state that resembles Alzheimer's symptoms.…”