Molecular, functional, and pathological aspects of TDP-43 fragmentation

Abstract

Transactive response DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in transcriptional regulation and RNA processing. It is linked to sporadic and familial amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is predominantly nuclear, but it translocates to the cytoplasm under pathological conditions. Cytoplasmic accumulation, phosphorylation, ubiquitination and truncation of TDP-43 are the main hallmarks of TDP-43 proteinopathies. Among these processes, the pathways leading to TDP-43 fragmentation remain poorly understood. We review here the molecular and biochemical properties of several TDP-43 fragments, the mechanisms and factors mediating their production, and their potential role in disease progression. We also address the presence of TDP-43 C-terminal fragments in several neurological disorders, including Alzheimer's disease, and highlight their respective implications. Finally, we discuss features of animal models expressing TDP-43 fragments as well as recent therapeutic strategies to approach TDP-43 truncation.

Keywords: Biological sciences; Molecular biology; Molecular interaction; Molecular physiology.

Graphical abstract

Figure 1

Effects of TDP-43 truncation in disease pathogenesis The scheme illustrates that TDP-43 functions normally as dimer or oligomer conformers in the nuclear compartment. However, upon translocation to the cytoplasm, truncation of TDP-43 promotes aggregation (gain-of-function). These aggregates hamper RNA stabilization in the cytoplasm leading to abnormal translational regulation, proteasomal degradation and sequestration/depletion of nuclear TDP-43 (loss-of-function). RP: RNA Polymerase complex.

Figure 2

Schematic representation of TDP-43 protein and its truncation sites For a Figure360 author presentation of Figure 2, see https://doi.org/10.1016/j.isci.2021.102459. TDP-43 includes multiple cleavage sites encompassing its NLS (nuclear localizing signal), RNA-binding motifs (RRM1 or RRM2), and Glycine-rich domain. Colored circles represent cleavage type, while the numbers inside indicate the amino acid residue from the N-terminal end. TDP-35 lacks functional NLS, while TDP-25 lacks NLS along with functional RRM domains leading to splicing and RNA-binding abnormalities.

Figure 3

Mechanisms of TDP-43 truncation through alternative splicing Center: The TDP-43 primary transcript generates a conventional mRNA splicing variant that encodes full-length TDP-43 in healthy neurons. However, under unknown conditions, at least two different kind of TDP-43 alternative transcripts can translate into N- or C-terminally truncated forms. Top: An alternative splicing event that removes most of the TARDBP exon 6 and integrates part of the 3′UTR leads to the generation of shortened TDP-43 (sTDP-43) isoforms. These splice variants lack the conventional C-terminus and acquire a distinct 18 amino acids C-terminal tail (brown rectangle). This new sequence contains a functional putative nuclear export sequence (NES) that promotes its cytosolic accumulation as well as sequestration of normal TDP-43, resulting in neurotoxicity. Bottom: A different splicing event gives rise to a C-terminal fragment through the use of an alternative translation initiation codon at Methionine-85 (M85) of the full-length TDP-43. The resulting isoform, referred to as Met⁸⁵-TDP-35, accumulates in cytoplasm where it can sequester endogenous TDP-43 and lead to neurotoxicity.

Figure 4

TDP-43 fragments accumulate in various neurodegenerative disorders Cytoplasmic accumulation of TDP-35 and TDP-25 CTFs can be found in primary (ALS and FTLD) and secondary (AD, CBD, PD, TBI) TDP-43 proteinopathies. Although TDP-43 pathology is also present in Huntington Disease and several Spinocerebellar ataxia (SCA) forms such as SCA2, SCA3 and SCA7, the presence of TDP-43 fragments in these polyglutamine disorders remain elusive.