The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology

Kasu, Yasar Arfat; Alemu, Samrawit; Lamari, Angela; Loew, Nicole; Brower, Christopher S.

doi:10.1128/mcb.00243-18

Cited by 12 publications

(21 citation statements)

References 86 publications

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“…In addition to the neuronal terminal differentiation deficits and gliosis in Vps35 Neurod6 mice, we also detected increases of P62/sequestosome 1 (SQSTM1), one factor that targets specific cargoes for autophagy, and Tdp-43, a DNA-RNA binding protein, in Vps35 Neurod6 cortical neurons (Figure 4) [33][34][35][36], both proteins often associated with the pathology of FTD [21,37]. To determine if expressing VPS35-mCherry fusion protein could reduce this brain pathology in Vps35 Neurod6 mice, we performed both coimmunostaining and Western blot analyses.…”

Section: Partial Reduction Of P62 and Tdp43 Proteins In Tgvps35 Neurod6 ; Ko Pubsmentioning

confidence: 90%

Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death

Zhao

Tang

Lee

et al. 2021

IJMS

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Vps35 (vacuolar protein sorting 35) is a key component of retromer that consists of Vps35, Vps26, and Vps29 trimers, and sortin nexin dimers. Dysfunctional Vps35/retromer is believed to be a risk factor for development of various neurodegenerative diseases. Vps35Neurod6 mice, which selectively knock out Vps35 in Neurod6-Cre+ pyramidal neurons, exhibit age-dependent impairments in terminal differentiation of dendrites and axons of cortical and hippocampal neurons, neuro-degenerative pathology (i.e., increases in P62 and Tdp43 (TAR DNA-binding protein 43) proteins, cell death, and reactive gliosis), and neonatal death. The relationships among these phenotypes and the underlying mechanisms remain largely unclear. Here, we provide evidence that expression of low level of VPS35-mCherry fusion protein in Vps35Neurod6 mice could diminish the phenotypes in an age-dependent manner. Specifically, we have generated a conditional transgenic mouse line, LSL-Vps35-mCherry, which expresses VPS35-mCherry fusion protein in a Cre-dependent manner. Crossing LSL-Vps35-mCherry with Vps35Neurod6 to obtain TgVPS35-mCherry, Vps35Neurod6 mice prevent the neonatal death and diminish the dendritic morphogenesis deficit and gliosis at the neonatal, but not the adult age. Further studies revealed that the Vps35-mCherry transgene expression was low, and the level of Vps35 mRNA comprised only ~5–7% of the Vps35 mRNA of control mice. Such low level of VPS35-mCherry could restore the amount of other retromer components (Vps26a and Vps29) at the neonatal age (P14). Importantly, the neurodegenerative pathology presented in the survived adult TgVps35-mCherry; Vps35Neurod6 mice. These results demonstrate the sufficiency of low level of VPS35-mCherry fusion protein to diminish the phenotypes in Vps35Neurod6 mice at the neonatal age, verifying a key role of neuronal Vps35 in stabilizing retromer complex proteins, and supporting the view for Vps35 as a potential therapeutic target for neurodegenerative diseases.

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Section: Partial Reduction Of P62 and Tdp43 Proteins In Tgvps35 Neurod6 ; Ko Pubsmentioning

confidence: 90%

Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death

Zhao

Tang

Lee

et al. 2021

IJMS

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“…The N-terminal region of each TDP-43 CTF may determine the specific pathway through which it is degraded (Kasu et al, 2018). Arginyltransferase (ATE), the enzyme responsible for post-translational arginylation, has been implicated in signaling processes required for the degradation of intracellular proteins by autophagy or UPS pathways.…”

Section: Degradation and Cellular Clearance Of Tdp-43 Ctfsmentioning

confidence: 99%

“…When expressed in mouse fibroblasts deficient for ATE, TDP-43 CTFs aggregate, suggesting that they are selectively degraded by the Arg/N-end rule pathway as a protective response to failing proteostasis and neurodegeneration (Brower et al, 2013). More recent work has shown that, whereas TDP-43 fragments beginning at residue 247 are degraded primarily by the Arg/N-end rule pathway, degradation of fragments with an N-terminal at residue 219 can occur independently of ATE (Kasu et al, 2018). Further dissection of the precise mechanisms of degradation of the different TDP-43 CTFs and the role of ATE is therefore warranted.…”

Section: Degradation and Cellular Clearance Of Tdp-43 Ctfsmentioning

confidence: 99%

The Pathobiology of TDP-43 C-Terminal Fragments in ALS and FTLD

2019

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During neurodegenerative disease, the multifunctional RNA-binding protein TDP-43 undergoes a vast array of post-translational modifications, including phosphorylation, acetylation, and cleavage. Many of these alterations may directly contribute to the pathogenesis of TDP-43 proteinopathies, which include most forms of amyotrophic lateral sclerosis (ALS) and approximately half of all frontotemporal dementia, pathologically identified as frontotemporal lobar degeneration (FTLD) with TDP-43 pathology. However, the relative contributions of the various TDP-43 post-translational modifications to disease remain unclear, and indeed some may be secondary epiphenomena rather than disease-causative. It is therefore critical to determine the involvement of each modification in disease processes to allow the design of targeted treatments. In particular, TDP-43 C-terminal fragments (CTFs) accumulate in the brains of people with ALS and FTLD and are therefore described as a neuropathological signature of these diseases. Remarkably, these TDP-43 CTFs are rarely observed in the spinal cord, even in ALS which involves dramatic degeneration of spinal motor neurons. Therefore, TDP-43 CTFs are not produced non-specifically in the course of all forms of TDP-43-related neurodegeneration, but rather variably arise due to additional factors influenced by regional heterogeneity in the central nervous system. In this review, we summarize how TDP-43 CTFs are generated and degraded by cells, and critique evidence from studies of TDP-43 CTF pathology in human disease tissues, as well as cell and animal models, to analyze the pathophysiological relevance of TDP-43 CTFs to ALS and FTLD. Numerous studies now indicate that, although TDP-43 CTFs are prevalent in ALS and FTLD brains, disease-related pathology is only variably reproduced in TDP-43 CTF cell culture models. Furthermore, TDP-43 CTF expression in both transgenic and viral-mediated in vivo models largely fails to induce motor or behavioral dysfunction reminiscent of human disease. We therefore conclude that although TDP-43 CTFs are a hallmark of TDP-43-related neurodegeneration in the brain, they are not a primary cause of ALS or FTLD.

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“…Other than the LCD, a segment of RRM2 ( 247 DLIIKGISVHI 257 ) has been shown to form several steric zipper polymorphs (Guenther et al, 2018b), suggesting this domain may also contribute to pathological aggregation at least when RRM2 is partially folded (Tavella et al, 2018). Additionally, the size of the TDP-43 fragments (35 kDa or 25 kDa) influences the aggregation and degradation pathways of TDP-43 (Kasu et al, 2018). On the other hand, the majority of evidence for TDP-43 to form amyloid comes from purified protein studies utilizing C-terminal fragments that are either pathological fragments (35 or 25 kDa) or just the LCD (amino acids 274–414), as well as just the RRMs or small segments thereof (Guenther et al, 2018b; Agrawal et al, 2019; Cao et al, 2019).…”

Section: Tdp-43 Prion Evidencementioning

confidence: 99%

Prion-Like Propagation of Protein Misfolding and Aggregation in Amyotrophic Lateral Sclerosis

McAlary

Plotkin

Yerbury

et al. 2019

Front. Mol. Neurosci.

119

103

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The discovery that prion protein can misfold into a pathological conformation that encodes structural information capable of both propagation and inducing severe neuropathology has revolutionized our understanding of neurodegenerative disease. Many neurodegenerative diseases with a protein misfolding component are now classified as “prion-like” owing to the propagation of both symptoms and protein aggregation pathology in affected individuals. The neuromuscular disorder amyotrophic lateral sclerosis (ALS) is characterized by protein inclusions formed by either TAR DNA-binding protein of 43 kDa (TDP-43), Cu/Zn superoxide dismutase (SOD1), or fused in sarcoma (FUS), in both upper and lower motor neurons. Evidence from in vitro, cell culture, and in vivo studies has provided strong evidence to support the involvement of a prion-like mechanism in ALS. In this article, we review the evidence suggesting that prion-like propagation of protein aggregation is a primary pathomechanism in ALS, focusing on the key proteins and genes involved in disease (TDP-43, SOD1, FUS, and C9orf72). In each case, we discuss the evidence ranging from biophysical studies to in vivo examinations of prion-like spreading. We suggest that the idiopathic nature of ALS may stem from its prion-like nature and that elucidation of the specific propagating protein assemblies is paramount to developing effective therapies.

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The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology

Cited by 12 publications

References 86 publications

Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death

Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death

The Pathobiology of TDP-43 C-Terminal Fragments in ALS and FTLD

Prion-Like Propagation of Protein Misfolding and Aggregation in Amyotrophic Lateral Sclerosis

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