Reduced cellular Ca2+ availability enhances TDP-43 cleavage by apoptotic caspases

Marco, Giovanni De; Lomartire, Annarosa; Mandili, Giorgia; Lupino, Elisa; Buccinnà, Barbara; Ramondetti, Cristina; Moglia, Cristina; Novelli, Francesco; Piccinini, Marco; Mostert, M.; Rinaudo, M.; Chiò, Adriano; Calvo, Andrea

doi:10.1016/j.bbamcr.2014.01.010

Cited by 21 publications

(21 citation statements)

References 61 publications

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“…In vitro experiments revealed that multiple caspases (caspases-3, -4, -7 and -9) cleave TDP-43 in cultured cells [ 6 , 11 , 26 , 29 , 42 ]. However, these in vitro experiments introduced caspases by transfection into cultured cells and did not tell us whether some of these caspases can endogenously determine the specific cleavage of TDP-43 in the primate brains.…”

Section: Resultsmentioning

confidence: 99%

Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains

et al. 2019

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The cytoplasmic accumulation of the nuclear TAR DNA-binding protein 43 (TDP-43) is a pathologic hallmark in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and other neurological disorders. However, most transgenic TDP-43 rodent models show predominant nuclear distribution of TDP-43 in the brain. By expressing mutant TDP-43 (M337V) in the brains of rhesus monkeys and mice, we verified that mutant TDP-43 is distributed in the cytoplasm of the monkey brain and that the majority of mutant TDP-43 remains in the nuclei of the mouse brain. The primate-specific caspase-4, but not mouse homologue caspase-11, could remove the NLS-containing N-terminal domain and generate fragmented TDP-43 that accumulates in the cytoplasm. Moreover, increased expression of caspase-4 in the monkey brain promotes the cytoplasmic accumulation of endogenous TDP-43, and suppressing caspase-4 reduces the cytoplasmic distribution of endogenous TDP-43 in cultured human neural cells. Our findings suggest that primate-specific caspase-4-mediated cleavage of TDP-43 accounts for its cytoplasmic mislocalization in the primate brains and may serve as a potential therapeutic target. Electronic supplementary material The online version of this article (10.1007/s00401-019-01979-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains

et al. 2019

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“…The exact functions of these truncated species remain unclear and are generally thought to be toxic, but have also been proposed to serve a protective role in the cell to promote TDP-43 clearance [59,63,73,[75][76][77][78][79][80]. It is important to recognize that other species of TDP-43 CTFs have been identified at 15-16 kDa, 22-25 kDa, and 33-37 kDa in ALS/ALS-FTLD, however due to low levels of reporting their prevalence in disease remains elusive [56,74,75,[81][82][83][84][85].…”

Section: Main Textmentioning

confidence: 99%

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk

Rousseaux

2020

Mol Neurodegeneration

254

170

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Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gainand loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclearto-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain-and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain-and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.

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“…Although the associated N-terminal fragments (NTFs) of TDP-43 are degraded quickly, the CTFs form aggregates that can also contain fulllength TDP-43. CTF35 is generated by caspase-3/7-mediated cleavage after Asp89, which is embedded in the consensus caspase-recognition motif [13][14][15][16] . Initially, Asp219 was suggested as the candidate cleavage site for CTF25; however, the estimated molecular weight of the fragment that comprises a.a. 220-414 is less than 25 kDa (refs 13,16,17).…”

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confidence: 99%

The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity

et al. 2015

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TAR DNA-binding protein of 43 kDa (TDP-43) and its C-terminal fragment of 25 kDa (CTF25) play critical roles in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although the overexpression of TDP-43 in cultured cells and animals results in the production of CTF25, the cleavage site that generates CTF25 and biological significance of the cleavage remain undetermined. Here we identify Asp174 as a cleavage site for CTF25. TDP-43 is cleaved initially after Asp174, which activates caspase-3/7 to accelerate TDP-43 fragmentation. Consequently, blockage of this cleavage results in a severe delay in TDP-43 clearance and prolonged necrotic cell death. We further show that the endoplasmic reticulum membrane-bound caspase-4 is the enzyme responsible for the cleavage after Asp174 and inhibition of caspase-4 activity slows TDP-43 fragmentation and reduces cell viability. These findings suggest that caspase-4-mediated cleavage after Asp174 is an initiator of TDP-43 clearance, which is required to avoid cell death induced by overexpressed TDP-43. A myotrophic lateral sclerosis (ALS) is one of the most devastating neurodegenerative diseases and is characterized by muscle weakness due to the degeneration of both upper and lower motor neurons. Although the pathogenic mechanism of ALS remains unresolved, the RNA-binding protein TDP-43 has been shown to accumulate in cytoplasmic inclusions in the affected regions of the spinal cord and brain in patients with ALS and frontotemporal lobar degeneration (FTLD), respectively 1,2 . Subsequently, mutations linked with ALS and FTLD have been identified in the gene that encodes TDP-43, which has confirmed the significance of TDP-43 in the pathogenesis of these diseases 3,4 . Most of these mutations occur within or near the carboxyl-terminal (C-terminal) glycine-rich domain (GRD) of TDP-43, except for the D169G point mutation that resides in RNA recognition motif 1 (refs 3,4). TDP-43 is normally localized predominantly in the nucleus. However, in ALS and FTLD patients with TDP-43-positive cytoplasmic inclusions, the protein is abnormally phosphorylated, ubiquitinated and truncated. This results in the accumulation of an B25-kDa C-terminal fragment (CTF25), in addition to other minor CTFs and the full-length TDP-43, in cytoplasmic aggregates. CTFs are hallmarks of forms of disease whose pathology is associated exclusively with abnormalities in TDP-43 and are observed in patients with not only ALS and FTLD but also Alzheimer's disease 5 . Amino-terminal (N-terminal) analysis of CTFs obtained from brain autopsies of patients with FTLD has resulted in the identification of three cleavage sites, Arg208, Asp219 and Asp247, which give rise to CTFs 6,7 . However, the expected sizes of the resulting CTFs are less than 25 kDa, which suggests that CTF25 is probably cleaved at a different position.TDP-43 is a widely expressed 414-amino acid (a.a.) protein comprised of two RNA recognition motifs (RRM1 at a.a. 106-176 and RRM2 at a.a. 191-262) and the GRD 8,9 . The chronic stabilization...

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Reduced cellular Ca2+ availability enhances TDP-43 cleavage by apoptotic caspases

Cited by 21 publications

References 61 publications

Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains

Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity

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