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.

Keywords: Alzheimer's disease; Neurodegenerative diseases; TDP-43; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; neurodegeneration.

Fig. 1

Domain structure, subcellular localization, post-translational modification, and function of TDP-43. (a) TDP-43 is a 414 amino acid protein, including an N-terminal domain (NTD, 1-102aa), two RNA recognition motifs (RRM1, 106-177aa and RRM2, 192-259aa) and a carboxy-terminal glycine-rich domain (CTD, 274-414aa). TDP-43 contains both a nuclear localization sequence (NLS, 82-98aa) and a nuclear export sequence (NES, 239-250aa). (b) The majority of TDP-43 resides in the nucleus under physiological conditions, while the remaining TDP-43 has been found to be present in other organelles, such as mitochondria, endoplasmic reticulum (ER), and exosomes. During stressful conditions, TDP-43 can be recruited to stress granules and hnRNPs. (c) The full-length 43 kDa TDP-43 is cleaved by caspases or calpain to generate ~35 kDa and 20-25 kDa fragments under disease conditions. The fragments and the full-length protein become aberrantly phosphorylated at serine residues 379, 403/404, and 409/410 in neurodegenerative disease affected brains. (d) TDP-43 exhibits multiple normal biological functions, predominantly those that regulate RNA pathways, including mRNA splicing, miRNA biogenesis, and transcription in nucleus, while it is also thought to play a role in mRNA transport, mRNA stability, and stress granule formation in the cytoplasm.