Pathomechanisms of TDP‐43 in neurodegeneration

Abstract

Neurodegeneration, a term that refers to the progressive loss of structure and function of neurons, is a feature of many neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). There is no cure or treatment available that can prevent or reverse neurodegenerative conditions. The causes of neurodegeneration in these diseases remain largely unknown; yet, an extremely small proportion of these devastating diseases are associated with genetic mutations in proteins involved in a wide range of cellular pathways and processes. Over the past decade, it has become increasingly clear that the most notable neurodegenerative diseases, such as ALS, FTLD, and AD, share a common prominent pathological feature known as TAR DNA-binding protein 43 (TDP-43) proteinopathy, which is usually characterized by the presence of aberrant phosphorylation, ubiquitination, cleavage and/or nuclear depletion of TDP-43 in neurons and glial cells. The role of TDP-43 as a neurotoxicity trigger has been well documented in different in vitro and in vivo experimental models. As such, the investigation of TDP-43 pathomechanisms in various major neurodegenerative diseases is on the rise. Here, after a discussion of stages of TDP-43 proteinopathy during disease progression in various major neurodegenerative diseases, we review previous and most recent studies about the potential pathomechanisms with a particular emphasis on ALS, FTLD, and AD, and discuss the possibility of targeting TDP-43 as a common therapeutic approach to treat neurodegenerative diseases.

Structure based analysis of protein cluster size for super-resolution microscopy in the nervous system

“…TDP-43 is a multifunctional DNA/RNA binding protein with an important role in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) 23 . Past studies have identified TDP-43 inclusion bodies as the pathological hallmark of ALS/FTLD and proposed that the clustering and self-aggregation of TDP-43 is involved in the pathogenesis of these neurodegenerative diseases 24,25 .…”

Induction Of Chronic Stress Reveals An Interplay Of Stress Granules And TDP-43 Pathological Aggregates In Human ALS Fibroblasts And iPSC-Neurons

“…It was shown that, when autophagy is impaired, SG disassembly is also affected because of accumulation of misfolded proteins including DRiPs [11], producing insoluble aggregates that disrupt neuronal homeostasis and promote ALS pathogenesis and neurodegeneration [12]. Indeed, defects in SG assembly and abnormal inclusions of TDP-43 protein have been described not only in ALS and FTD, but also in other neurodegenerative diseases, including spinocerebellar ataxia, Alzheimer's, Parkinson's and Huntington diseases [48], suggesting that TDP-43 may have a common pivotal role in neurodegeneration.…”

Endoplasmic Reticulum Stress Signalling Induces Casein Kinase 1-Dependent Formation of Cytosolic TDP-43 Inclusions in Motor Neuron-Like Cells

“…The mechanisms underlying TDP-43 aggregation in sporadic MND are incompletely characterized, although phosphorylation of TDP-43 is likely to be important [20]. TDP-43 is a substrate for a number of protein kinasescasein kinase 1 (CK1) has been identified as a direct TDP-43 kinase, including at S409/410 [21][22][23][24][25], and its overexpression can induce TDP-43 phosphorylation [26].…”