Clinical Aspects of TDP‐43 Proteinopathy, Neurofilament Inclusion Body Disease and Dementias Lacking Distinctive Proteinopathy

Josephs, Keith A.

doi:10.1016/s0072-9752(07)01235-3

Cited by 3 publications

(6 citation statements)

References 45 publications

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“…It appears that the changes in TDP‐43 are insufficient to induce tau pathology under these conditions. However, several studies have shown that AD patients with TDP‐43 pathology showed greater memory loss and cognitive impairment , leading to TDP‐43 that is considered as the third protein of AD . Here, we found that TDP‐43 phosphorylation by CK1ε promoted its cytoplasmic aggregation, made it unable to promote tau mRNA instability and tau exon 10 inclusion.…”

Section: Discussionmentioning

confidence: 64%

“…TDP-43 pathology is originally reported to be associated with ALS and FTLD (44). Subsequent studies suggested TDP-43 pathology presented in 2/3 of the brains of patients with AD (2,34), and is associated with a higher likelihood of the clinical expression of clinical Alzheimer's-type dementia, including with greater memory loss, cognitive impairment and dementia, naming and functional decline, and hippocampal atrophy (30,31,33,34,42). In the present study, we observed robust intraneuronal cytoplasmic inclusion and dystrophic neurites stained with anti-TDP-43 in AD brains.…”

Section: Discussionmentioning

confidence: 99%

“…TDP‐43 proteinopathy has been observed in >57% of AD cases . TDP‐43 is considered as the third protein linked to AD . We recently reported that TDP‐43 regulates the tau mRNA processing, including promoting tau mRNA instability via acting on its 3′‐UTR and tau exon 10 inclusion .…”

Section: Discussionmentioning

confidence: 99%

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Elevation of casein kinase 1ε associated with TDP‐43 and tau pathologies in Alzheimer's disease

Tan

et al. 2019

Brain Pathology

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Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid β plaques and intraneuronal neurofibrillary tangles of hyperphosphorylated microtubule‐associated protein tau in the brain. Aggregation of transactive response DNA‐binding protein of 43 kDa (TDP‐43) in the neuronal cytoplasm is another feature of AD. However, how TDP‐43 is associated with AD pathogenesis is unknown. Here, we found that casein kinase 1ε (CK1ε) phosphorylated TDP‐43 at Ser403/404 and Ser409/410. In AD brains, the level of CK1ε was dramatically increased and positively correlated with the phosphorylation of TDP‐43 at Ser403/404 and Ser409/410. Overexpression of CK1ε promoted its cytoplasmic aggregation and suppressed TDP‐43‐promoted tau mRNA instability and tau exon 10 inclusion, leading to an increase of tau and 3R‐tau expressions. Levels of CK1ε and TDP‐43 phosphorylation were positively correlated with the levels of total tau and 3R‐tau in human brains. Furthermore, we observed, in pilot immunohistochemical studies, that the severe tau pathology was accompanied by robust TDP‐43 pathology and a high level of CK1ε. Taken together, our findings suggest that the elevation of CK1ε in AD brain may phosphorylate TDP‐43, promote its cytoplasmic aggregation and suppress its function in tau mRNA processing, leading to acceleration/exacerbation of tau pathology. Thus, the elevation of CK1ε may link TDP‐43 to tau pathogenesis in AD brain.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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Elevation of casein kinase 1ε associated with TDP‐43 and tau pathologies in Alzheimer's disease

Tan

et al. 2019

Brain Pathology

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“…It appears that the changes in TDP‐43 alone are insufficient to induce tau pathology under these conditions. However, several studies have reported that individuals of AD with TDP‐43 pathology show greater memory loss and cognitive impairment than AD cases without TDP‐43 pathology (Josephs, 2008; Josephs et al., 2015), and TDP‐43 is therefore considered the third protein associated with AD (Josephs, Whitwell, et al., 2014). In the present study, we found that CK1ε phosphorylates TDP‐43 and promotes its cytoplasmic aggregation and nuclear depletion and makes it unable to promote tau mRNA instability and tau exon 10 inclusion.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of trans‐active response DNA‐binding protein‐of 43 kDa promotes its cytoplasmic aggregation and modulates its function in tau mRNA stability and exon 10 alternative splicing

Zhou

Shen

et al. 2021

Journal of Neurochemistry

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Trans‐active response DNA‐binding protein of 43 kDa (TDP‐43) promotes tau mRNA instability and tau exon 10 inclusion. Aggregation of phosphorylated TDP‐43 is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Casein kinase 1ε (CK1ε) phosphorylates TDP‐43 at multiple sites, enhances its cytoplasmic aggregation, and modulates its function in tau mRNA processing. To determine roles of TDP‐43 site‐specific phosphorylation in its localization, aggregation, and function in tau mRNA processing, TDP‐43 was mutated to alanine or aspartic acid at Ser379, Ser403/404, or Ser409/410 to block or mimic phosphorylation. Site‐specific phosphorylation of TDP‐43 and its mutants by CK1ε was studied in vitro and in cultured cells. Cytoplasmic and nuclear TDP‐43 and phospho‐TDP‐43 were analyzed by western blots. Aggregation of TDP‐43 was assessed by immunostaining and level of radioimmunoprecipitation assay buffer‐insoluble TDP‐43. Green florescent protein tailed with tau 3′‐untranslated region and mini‐tau gene pCI/SI9‐LI10 were used to study tau mRNA stability and alternative splicing of tau exon 10. We found that phospho‐blocking mutations of TDP‐43 at Ser379, Ser403/404, or Ser409/410 were not effectively phosphorylated by CK1ε. Compared with TDP‐43, higher level of phosphorylated TDP‐43 in the cytoplasm was observed. Phospho‐mimicking mutations at these sites enhanced cytoplasmic aggregation of TDP‐43. Green florescent protein expression was not inhibited by phospho‐blocking mutants of TDP‐43, but tau exon 10 inclusion was further enhanced by phospho‐blocking mutations at Ser379 and Ser403/404. Phosphorylation of TDP‐43 at Ser379, Ser403/404, or Ser409/410 primes its phosphorylation by CK1ε, promotes TDP‐43 cytoplasmic aggregation, and modulates its function in tau mRNA processing in site‐specific manner.

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“…Within the spectrum of FTDs, a broad distinction can be made between those with underlying tau pathology versus those with the newly discovered TDP‐43 protein abnormalities, labeled previously with ubiquitin and termed FTD‐U 15. The combination in this case of severe cortical pathology with features of PSP is much more in keeping with an underlying tauopathy.…”

Section: Discussant 2 (John Hodges)mentioning

confidence: 99%

Postural instability, frontotemporal dementia, and ophthalmoplegia: Clinicopathological case

et al. 2011

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A 56-year-old man presented with gait disturbance, personality change, and behavioral disturbances. He subsequently developed falls, postural instability, and axial rigidity. The cognitive problems progressed and he developed aphasia and later eye movement abnormalities. He died after 9 years of disease. Experts discuss the syndromal diagnosis and predict the underlying pathology. The pathological diagnosis is given and clinical learning points are considered.

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Clinical Aspects of TDP‐43 Proteinopathy, Neurofilament Inclusion Body Disease and Dementias Lacking Distinctive Proteinopathy

Cited by 3 publications

References 45 publications

Elevation of casein kinase 1ε associated with TDP‐43 and tau pathologies in Alzheimer's disease

Elevation of casein kinase 1ε associated with TDP‐43 and tau pathologies in Alzheimer's disease

Phosphorylation of trans‐active response DNA‐binding protein‐of 43 kDa promotes its cytoplasmic aggregation and modulates its function in tau mRNA stability and exon 10 alternative splicing

Postural instability, frontotemporal dementia, and ophthalmoplegia: Clinicopathological case

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