Disease-Associated Mutations of TDP-43 Promote Turnover of the Protein Through the Proteasomal Pathway

Araki, Wataru; Minegishi, Seiji; Motoki, Kazumi; Kume, Hideaki; Hohjoh, Hirohiko; Araki, Yumiko M.; Tamaoka, Akira

doi:10.1007/s12035-014-8644-6

Cited by 19 publications

(16 citation statements)

References 70 publications

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“…Next, we investigated the mechanism of HSF1‐mediated protection against stress‐induced insolubility of TDP‐43. Accumulation of TDP‐43 into ubiquitin‐positive inclusions in ALS and frontotemporal lobar degenerated (FTLD) brains have implicated the UPS in TDP‐43 degradation or pathogenesis (Araki et al, ; Liu et al, ). We used a GFP reporter system that allowed us to quantify global rates of UPS proteolysis (Dantuma et al, ).…”

Section: Resultsmentioning

confidence: 99%

Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells

Lin

Folorunso

Taglialatela

et al. 2016

J of Neuroscience Research

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TAR DNA binding protein 43 (TDP-43) is a nuclear protein that has been shown to have altered homeostasis in the form of neuronal nuclear and cytoplasmic aggregates in some familial and almost all cases of sporadic amyotrophic lateral sclerosis as well as 51% of frontotemporal lobar degeneration and 57% of Alzheimer's disease cases. Heat shock proteins (HSPs), such as HSP70, recognize misfolded or aggregated proteins and refold, disaggregate, or turn them over and are upregulated by the master transcription factor heat shock factor 1 (HSF1). Here, we explore the effect of HSF1 overexpression on proteotoxic stress-related alterations in TDP-43 solubility, proteolytic processing, and cytotoxicity. HSF1 overexpression reduced TDP-43-positive puncta concomitantly with upregulating HSP70 and HSP90 protein levels. HSF1 overexpression or pharmacological activation sustained TDP-43 solubility and significantly reduced truncation of TDP-43 in response to inhibition of the proteasome with Z-Leu-Leu-Leu-al, and this was reversed by HSF1 inhibition. HSF1 activation conferred protection against toxicity associated with TDP-43 C-terminal fragments without globally increasing the activity of the ubiquitin proteasome system (UPS) while concomitantly reducing the induction of autophagy, suggesting that HSF1 protection is an early event. In support of this, inhibition of HSP70 ATPase activity further reduced TDP-43 solubility. HSF1 knockout significantly increased TDP-43 insolubility and accelerated TDP-43 fragmentation in response to proteotoxic stress. Overall, this study shows that HSF1 overexpression protects against TDP-43 pathology by upregulation of chaperones, especially HSP70, rather than enhancing autophagy or the UPS during times of proteotoxic stress. © 2016 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells

Lin

Folorunso

Taglialatela

et al. 2016

J of Neuroscience Research

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“…Chloroquine inhibits autophagy by inhibiting the acidification of autophagosome and maturation of autolysosome, resulting in the accumulation of autophagic vesicles and the inhibition of autolysosomal protein degradation. The pharmacological inhibition of autophagy by chloroquine has been previously tested in in vitro models of ALS, but to date no data has been registered in skeletal muscle cells[ 38 ]. After treating with chloroquine the explants from skeletal muscles, significant LC3-II increased levels were observed, suggesting that autophagy was still activated.…”

Section: Discussionmentioning

confidence: 99%

Time-Point Dependent Activation of Autophagy and the UPS in SOD1G93A Mice Skeletal Muscle

et al. 2015

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Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by a selective loss of motor neurons together with a progressive muscle weakness. Albeit the pathophysiological mechanisms of the disease remain unknown, growing evidence suggests that skeletal muscle can be a target of ALS toxicity. In particular, the two main intracellular degradation mechanisms, autophagy and the ubiquitin-proteasome degradative system (UPS) have been poorly studied in this tissue. In this study we investigated the activation of autophagy and the UPS as well as apoptosis in the skeletal muscle from SOD1G93A mice along disease progression. Our results showed a significant upregulation of proteasome activity at early symptomatic stage, while the autophagy activation was found at presymptomatic and terminal stages. The mRNA upregulated levels of LC3, p62, Beclin1, Atg5 and E2f1 were only observed at symptomatic and terminal stages, which reinforced the time-point activation of autophagy. Furthermore, no apoptosis activation was observed along disease progression. The combined data provided clear evidence for the first time that there is a time-point dependent activation of autophagy and UPS in the skeletal muscle from SOD1G93A mice.

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“…The ALS-associated mutations in UBQLN2 cause impaired autophagy and induce increased overall TDP-43 levels and promote the TDP-43 aggregation in the neuronal cells (Osaka et al, 2016). Araki et al have found that the disease-associated TDP-43 mutants like G298S and A382T, are more rapidly turned over than the wild-type protein, through the ubiquitin-proteasome system, thus highlighting the pathological relevance of the TDP-43 proteolysis and clearance (Araki et al, 2014).…”

Section: Emerging Mechanisms Of Tdp-43-induced Cytotoxicitymentioning

confidence: 99%

Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis

Prasad

Bharathi

Sivalingam

et al. 2019

Front. Mol. Neurosci.

526

573

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TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA binding protein involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits act as inclusion bodies in the brain and spinal cord of patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While the majority of ALS cases (90–95%) are sporadic (sALS), among familial ALS cases 5–10% involve the inheritance of mutations in the TARDBP gene and the remaining (90–95%) are due to mutations in other genes such as: C9ORF72, SOD1, FUS , and NEK1 etc. Strikingly however, the majority of sporadic ALS patients (up to 97%) also contain the TDP-43 protein deposited in the neuronal inclusions, which suggests of its pivotal role in the ALS pathology. Thus, unraveling the molecular mechanisms of the TDP-43 pathology seems central to the ALS therapeutics, hence, we comprehensively review the current understanding of the TDP-43's pathology in ALS. We discuss the roles of TDP-43's mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS. Also, we evaluate TDP-43's amyloid-like in vitro aggregation, its physiological vs. pathological oligomerization in vivo , liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP-43 inclusions. Finally, we describe the various evolving TDP-43-induced toxicity mechanisms, such as the impairment of endocytosis and mitotoxicity etc. and also discuss the emerging strategies toward TDP-43 disaggregation and ALS therapeutics.

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Disease-Associated Mutations of TDP-43 Promote Turnover of the Protein Through the Proteasomal Pathway

Cited by 19 publications

References 70 publications

Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells

Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells

Time-Point Dependent Activation of Autophagy and the UPS in SOD1G93A Mice Skeletal Muscle

Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis

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