Concurrence of TDP-43, tau and α-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies

Higashi, Shinji; Iseki, Eizo; Yamamoto, Ryo; Minegishi, Michiko; Hino, Hiroaki; Fujisawa, Kotaro; Togo, Takashi; Katsuse, Omi; Uchikado, Hirotake; Furukawa, Yoshiko; Kosaka, Kenji; Arai, Heii

doi:10.1016/j.brainres.2007.09.048

Cited by 368 publications

(327 citation statements)

References 47 publications

Supporting

Mentioning

283

Contrasting

Unclassified

Order By: Relevance

“…TDP-43 has been discovered in both sporadic and familial AD [46][47][48] , and our seeding results showed that TDP-43 oligomers can interact and influence Ab fibrillization. The increased Ab assembly in the presence of TDP-43 could result from a seeding effect that generates new Ab assemblies such as Ab*56 and larger aggregates or formation of cross-linked TDP-43 and Ab complexes.…”

Section: Discussionmentioning

confidence: 53%

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

et al. 2014

View full text Add to dashboard Cite

Proteinaceous inclusions are common hallmarks of many neurodegenerative diseases. TDP-43 proteinopathies, consisting of several neurodegenerative diseases, including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS), are characterized by inclusion bodies formed by polyubiquitinated and hyperphosphorylated full-length and truncated TDP-43. The structural properties of TDP-43 aggregates and their relationship to pathogenesis are still ambiguous. Here we demonstrate that the recombinant full-length human TDP-43 forms structurally stable, spherical oligomers that share common epitopes with an anti-amyloid oligomer-specific antibody. The TDP-43 oligomers are stable, have exposed hydrophobic surfaces, exhibit reduced DNA binding capability and are neurotoxic in vitro and in vivo. Moreover, TDP-43 oligomers are capable of cross-seeding Alzheimer's amyloid-b to form amyloid oligomers, demonstrating interconvertibility between the amyloid species. Such oligomers are present in the forebrain of transgenic TDP-43 mice and FTLD-TDP patients. Our results suggest that aside from filamentous aggregates, TDP-43 oligomers may play a role in TDP-43 pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 53%

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Moreover, a 400% increase of GRN expression has been observed in the spinal cord of patients with ALS [Malaspina et al, 2001] and Creutzfeldt-Jakob disease (CJD) [Baker and Manuelidis, 2003], most likely as a result of the activation of microglia. In AD and Lewy-body related diseases, TDP-43 immunoreactivity was also observed [Amador-Ortiz et al, 2007;Nakashima-Yasuda et al, 2007;Higashi et al, 2007]. In addition, FTLD and AD are sometimes difficult to differentiate at diagnosis and their key symptoms can be accompanied by parkinsonism, also occuring in FTLD patients carrying a GRN null mutation Mackenzie, 2007].…”

Section: Introductionmentioning

confidence: 99%

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

View full text Add to dashboard Cite

Communicated by Mark H. PaalmanMutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), [1373][1374][1375][1376][1377][1378][1379][1380][1381][1382][1383][1384][1385][1386] 2008.

show abstract

“…We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening. (1)(2)(3)(4). Mutations in the gene encoding TDP-43 (TARDBP) have been identified in familial and sporadic ALS (5)(6)(7)(8).…”

mentioning

confidence: 99%

Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability

Bilican

Serio²,

Barmada

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

311

292

View full text Add to dashboard Cite

Transactive response protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening. Several in vitro and in vivo models established the toxicity of ALS-associated TDP-43 mutations, although the underlying mechanism is unclear (9, 10). Most cellular and animal models of ALS and FTLD-TDP pathogenesis involve overexpression of TDP-43 in nonneuronal or nonhuman cells and cannot be used to investigate the selective vulnerability of neurons or key molecular events that are unique to human cells. By contrast, induced pluripotent stem cells (iPSCs) (11-14) coupled with defined in vitro differentiation protocols (15-20) offer a model system to investigate disease mechanisms in a more physiological context. Here, we report the pathological effects of endogenous mutant TDP-43 in iPSC-derived human neurons from an ALS patient carrying the M337V mutation.

show abstract

Concurrence of TDP-43, tau and α-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies

Cited by 368 publications

References 47 publications

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability

Contact Info

Product

Resources

About