TDP-43 as a therapeutic target in neurodegenerative diseases: Focusing on motor neuron disease and frontotemporal dementia.

Autor: Babazadeh A; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia. Electronic address: afshin.babazadeh@mq.edu.au., Rayner SL; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia. Electronic address: Stephanie.Rayner@mq.edu.au., Lee A; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia. Electronic address: Albert.Lee@mq.edu.au., Chung RS; Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia. Electronic address: Roger.Chung@mq.edu.au.
Jazyk: angličtina
Zdroj: Ageing research reviews [Ageing Res Rev] 2023 Dec; Vol. 92, pp. 102085. Date of Electronic Publication: 2023 Oct 08.
DOI: 10.1016/j.arr.2023.102085
Abstrakt: A common feature of adult-onset neurodegenerative diseases is the presence of characteristic pathological accumulations of specific proteins. These pathological protein depositions can vary in their protein composition, cell-type distribution, and intracellular (or extracellular) location. For example, abnormal cytoplasmic protein deposits which consist of the TDP-43 protein are found within motor neurons in patients with amyotrophic lateral sclerosis (ALS, a common form of motor neuron disease) and frontotemporal dementia (FTD). The presence of these insoluble intracellular TDP-43 inclusions suggests that restoring TDP-43 homeostasis represents a potential therapeutical strategy, which has been demonstrated in alleviating neurodegenerative symptoms in cell and animal models of ALS/FTD. We have reviewed the mechanisms that lead to disrupted TDP-43 homeostasis and discussed how small molecule-based therapies could be applied in modulating these mechanisms. This review covers recent advancements and challenges in small molecule-based therapies that could be used to clear pathological forms of TDP-43 through various protein homeostasis mechanisms and advance the way towards finding effective therapeutical drug discoveries for neurodegenerative diseases characterized by TDP-43 proteinopathies, especially ALS and FTD. We also consider the wider insight of these therapeutic strategies for other neurodegenerative diseases.
Competing Interests: Declaration of Competing Interest None.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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