The Role of TDP-43 in Neurodegenerative Disease

Liao, Yan-Zhe; Ma, Jing; Dou, Jie-Zhi

doi:10.1007/s12035-022-02847-x

Cited by 42 publications

(23 citation statements)

References 161 publications

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“…In normal physiological conditions, TDP-43 predominantly resides in the nucleus but can actively engage in biochemical reactions in the cytoplasm by shuttling between the cytoplasm and the nucleus. [17] TDP-43 is shown to link to the vast majority of ALS cases, accounting for approximately 97 % of them. [18] A common neuropathological hallmark is the development of cytoplasmic TDP-43 inclusion bodies, accompanied by the reduction of the typical TDP-43 presence in the nucleus.…”

Section: Amyloid Beta Peptide (Aβ)mentioning

confidence: 98%

A tale of dual functions of SERF family proteins in regulating amyloid formation

Qi,

Peng,

Wang

et al. 2024

ChemBioChem

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The abnormal aggregation of proteins is a significant pathological hallmark of diseases, such as the amyloid formation associated with fused in sarcoma protein (FUS) in frontotemporal lobar degeneration and amyotrophic lateral sclerosis diseases. Understanding which cellular components and how these components regulate the process of abnormal protein aggregation in living organisms is crucial for the prevention and treatment of neurodegenerative diseases. MOAG‐4/SERF is a conserved family of proteins with rich positive charged residues, which was initially identified as an enhancer for the formation of amyloids in C. elegans. Knocking out SERF impedes the amyloid formation of various proteins, including α‐synuclein and β‐amyloid, which are linked to Parkinson's and Alzheimer's diseases, respectively. However, recent studies revealed SERF exhibited dual functions, as it could both promote and inhibit the fibril formation of the neurodegenerative disease‐related amyloidogenic proteins. The connection between functions and structure basis of SERF in regulating the amyloid formation is still unclear. This review will outline the hallmark proteins in neurodegenerative diseases, summarize the contradictory role of the SERF protein family in promoting and inhibiting the aggregation of neurodegenerative proteins, and finally explore the potential structural basis and functional selectivity of the SERF protein.

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Section: Amyloid Beta Peptide (Aβ)mentioning

confidence: 98%

A tale of dual functions of SERF family proteins in regulating amyloid formation

Qi,

Peng,

Wang

et al. 2024

ChemBioChem

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“…TDP-43 -a multifunctional protein with RNA/DNA binding activities and physiological localization in the cell nucleus-has been found to display functional abnormalities, including its identification as a major component of cytosolic intraneuronal and glial inclusions, in virtually all ALS patients 9,10 and a number of ALS animal models 11,12 . Thus, TDP-43 is currently thought to represent a common molecular hub in these disorders, where different pathogenic mechanisms may converge and finally result in neurotoxic cellular outcomes 13 .…”

Section: Introductionmentioning

confidence: 99%

MAPK/MAK/MRK overlapping kinase (MOK) controls microglial inflammatory/type-I IFN responses via Brd4 and is involved in ALS

Perez-Cabello

Franco

Silvera-Carrasco

et al. 2023

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease affecting motor neurons and characterized by microglia-mediated neurotoxic inflammation whose underlying mechanisms remain incompletely understood. In this work we reveal that MAPK/MAK/MRK overlapping kinase (MOK), with unknown physiological substrate/s, displays an immune-related function, namely by controlling inflammatory and type-I IFN responses in microglia which result neurotoxic to primary motor neurons. Moreover, we uncover the epigenetic reader bromodomain-containing protein 4 (Brd4) as the first molecule regulated by MOK, by promoting Ser492-phospho-Brd4 levels. We further demonstrate that MOK regulates Brd4 functions by supporting Brd4 binding to cytokine gene promoters, therefore enabling innate immune responses. Remarkably, we show that MOK levels are increased in ALS spinal cord, particularly in microglial cells, and that administration of a chemical MOK-inhibitor to ALS model mice can suppress microglial activation and delay disease onset, pointing to a pathophysiological role of MOK kinase in ALS and neuroinflammation.

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“…Of these proteins, TDP-43 is the most extensively studied ALS-associated RBP since its dysregulation has been directly associated with neuronal death in vitro and in vivo 14,15 and TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCIs) are observed in 97% of ALS cases 16 . TDP-43 is also the main pathological component of a group of diseases called TDP-43 proteinopathies which include frontotemporal dementia (FTD) and Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE) 17 . Because of this, there is a special interest in targeting TDP-43 as a therapeutic approach 18–20 .…”

Section: Introductionmentioning

confidence: 99%

Mitigation of TDP-43-induced toxic phenotype by expression of RGNEF N-terminal fragment in ALS models

Droppelmann,

Campos-Melo,

Noches

et al. 2023

Preprint

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Aggregation of the RNA-binding protein (RBP) TDP-43 is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Since TDP-43 aggregation and dysregulation are causative of neuronal death, there is a special interest in targeting this protein as a therapeutic approach. Previously, we found that TDP-43 extensively co-aggregated with the dual function protein (GEF (guanine exchange factor) and RBP) rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that a N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs (RRM) of TDP-43 competing with RNA, and that the IPT/TIG domain of NF242 is essential for this interaction. Genetical expression of NF242 in a fruit fly ALS model overexpressing TDP-43 suppressed the neuropathological phenotype increasing lifespan, abolishing motor defects, and preventing neurodegeneration. Intracerebroventricular injections of AAV9/NF242 in a severe TDP-43 murine model (rNLS8) improved lifespan and motor phenotype, and decreased neuroinflammation markers. Our results demonstrate an innovative way to target TDP-43 proteinopathies using a protein fragment with affinity for TDP-43, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD.

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The Role of TDP-43 in Neurodegenerative Disease

Cited by 42 publications

References 161 publications

A tale of dual functions of SERF family proteins in regulating amyloid formation

A tale of dual functions of SERF family proteins in regulating amyloid formation

MAPK/MAK/MRK overlapping kinase (MOK) controls microglial inflammatory/type-I IFN responses via Brd4 and is involved in ALS

Mitigation of TDP-43-induced toxic phenotype by expression of RGNEF N-terminal fragment in ALS models

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