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.

Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity

“…TDP-43 CTFs are known to form condensates in the cell (Berning & Walker, 2019; Chhangani et al ., 2021). Here, we showed that the 220–262 region of tRRM2 on the N-terminal side of the GRR has an important role in the formation of the condensates.…”

“…In ALS and FTLD pathology, not only full-length TDP-43 but also TDP-43 CTFs are included in the condensates in the brain, but are rarely detected in the spinal cord (Neumann et al , 2006; Smethurst et al , 2016). Therefore, it has been proposed that TDP-43 CTFs may not be a prerequisite for neurodegeneration (Berning & Walker, 2019; Lee et al , 2011); however, TDP-43 fragmentation and its CTFs are a potential therapeutic target because ectopic expression of TDP-43 CTFs leads to various dysfunctions such as impaired autophagy and proteasome function, reducing functional dimerization/oligomerization of TDP-43, reduced motor function, and cell death, in cellular models and also in animal models (Caccamo et al , 2015; Chhangani et al , 2021; Fazal et al , 2021; Kitamura et al , 2016; Wang et al , 2015). Consequently, the proteotoxic mechanism of TDP-43 CTFs remains elusive.…”

Emerging Roles of lncRNAs Regulating RNA-Mediated Type-I Interferon Signaling Pathway

“…Thus, the activity of TDP35 positively regulated IRF3-directed IFN signaling. LncRNA Malat1 binds directly to the RRM1 domain of TDP43 in the nucleus to block its cleavage (84). Upon viral infection, Malat1 expression is downregulated and TDP43 is released to become TDP35 (85).…”

TDP-43 and ER Stress in Neurodegeneration: Friends or Foes?

“…One of the more prominent hallmarks of TDP-43-dependent neuropathology is the presence of TDP-43 C-terminal fragments (CTFs) generated by caspases and calpain proteases (Yang et al, 2010 ; Zhang et al, 2013 ). Overexpression of CTFs between 15 kDa and 35 kDa often recapitulate many of the pathological features of TDP-43 proteinopathies and they are commonly detected in vitro and in vivo (Chhangani et al, 2021 ). For instance, expression of CTF-25 in neural cells resulted in co-aggregation with full-length TDP-43 and impaired neurite growth in the mouse motor neuron-like hybrid cell line NSC-34 (Yang et al, 2010 ).…”