TDP-43 Variants of Frontotemporal Lobar Degeneration

Bigio, Eileen H.

doi:10.1007/s12031-011-9545-z

Cited by 22 publications

(14 citation statements)

References 38 publications

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“…In addition, the stability of the fulllength Myc-hTDP-43(D89A) mutant, which is resistant to caspase 3 cleavage, is also higher than the full-length wild-type Myc-hTDP-43 in transfected N2a cells ( (Zhang et al, 2007), is a necessary intermediate step for degradation of the majority of TDP-43 protein through the processing of the TDP-25 and TDP-35 fragments by UPS, macroautophagy and CMA. In TDP-43 proteinopathies as caused by gene mutations or environmental stresses (Bigio, 2011;Boillé e et al, 2006;Braun et al, 2011;Chen-Plotkin et al, 2008;Kwong et al, 2007;Mishra et al, 2007;Neumann, 2009), the degradation of the different TDP-43 species is somehow inhibited. The proteolytic cleavage of TDP-43 into TDP-25 and TDP-35 is also enhanced in the diseased cells (Arai et al, 2006;Kabashi et al, 2008;Neumann et al, 2006;Sreedharan et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Metabolism and mis-metabolism of the neuropathological signature protein TDP-43

Huang

Bose

Majumder

et al. 2014

Journal of Cell Science

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BSTRACT TDP-43 (also known as TARDBP) is a pathological signature protein of neurodegenerative diseases, with TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD)-TDP and amyotrophic lateral sclerosis (ALS)-TDP. These TDP-43 proteinopathies are characterized by cytoplasmic insoluble TDP-43-positive aggregates in the diseased cells, the formation of which requires the seeding of TDP-25 fragment generated by caspase cleavage of TDP-43. We have investigated the metabolism and mis-metabolism of TDP-43 in cultured cells and found that endogenous and exogenously overexpressed TDP-43 is degraded not only by the ubiquitin proteasome system (UPS) and macroautophagy, but also by the chaperone-mediated autophagy (CMA) mediated through an interaction between Hsc70 (also known as HSPA8) and ubiquitylated TDP-43. Furthermore, proteolytic cleavage of TDP-43 by caspase(s) is a necessary intermediate step for degradation of the majority of the TDP-43 protein, with the TDP-25 and TDP-35 fragments being the main substrates. Finally, we have determined the threshold level of the TDP-25 fragment that is necessary for formation of the cytosolic TDP-43-positive aggregates in cells containing the full-length TDP-43 at an elevated level close to that found in patients with TDP-43 proteinopathies. A comprehensive model of the metabolism and mismetabolism of TDP-43 in relation to these findings is presented.

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Section: Discussionmentioning

confidence: 99%

Metabolism and mis-metabolism of the neuropathological signature protein TDP-43

Huang

Bose

Majumder

et al. 2014

Journal of Cell Science

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“…Although TDP‐43 pathology is a hallmark pathology associated with a subtype of fronto‐temporal lobar degeneration (FTLD)‐TDP and motor neuron disease , it is also present in Alzheimer's disease (AD) . The neuropathological hallmark lesions of AD include intracytoplasmic neurofibrillary tangles (NFTs) and dendritic and axonal neuropil threads (NTs) that are composed of aggregated hyperphosphorylated microtubule associated tau (HP‐τ) , extracellular depositions of amyloid‐β protein (Aβ) and neuritic plaques consisting of Aβ and HP‐τ in DNs .…”

Section: Introductionmentioning

confidence: 99%

TDP‐43 pathology in Alzheimer's disease, dementia with Lewy bodies and ageing

et al. 2016

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Intracellular inclusions consisting of TAR DNA binding protein-43 (TDP-43 pathology) are present in up to 57% of Alzheimer's disease (AD) cases and follow a distinct topographical pattern of progression described in the TDP-43 in AD staging scheme. This scheme has not been applied to the assessment of TDP-43 pathology in dementia with Lewy bodies (DLB) and aged controls. We investigated TDP-43 pathology prevalence and severity in AD, DLB, mixed AD/DLB (Mx AD/DLB) and aged controls. One hundred and nineteen human post-mortem brains were included, neuropathologically diagnosed as AD: 46, DLB: 15, Mx AD/DLB: 19 and aged controls: 39. Paraffin sections inclusive of the amygdala, hippocampus, striatum and neocortex were immunohistochemically stained with antibodies against phosphorylated TDP-43 and staged according to the TDP-43 in AD staging scheme. TDP-43 pathology was present in all groups: AD: 73.9%, DLB: 33.3%, Mx AD/DLB: 52.6% and controls: 17.9%. Prevalence of TDP-43 pathology was significantly higher in AD and Mx AD/DLB compared to controls. In controls, higher age at death was associated with prevalence of TDP-43 pathology and higher TDP-43 in AD stage, suggesting that this type of TDP-43 pathology may partly be an age-associated phenomenon. Significantly higher prevalence of TDP-43 pathology in the AD group indicates that AD pathology possibly triggers and aggravates TDP-43 pathology. The validity of the TDP-43 in AD staging scheme is not limited to AD and should be applied to assess TDP-43 pathology in post mortem brains of aged individuals to further elucidate the role of TDP-43 pathology in age associated neurodegeneration.

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“…The transactive response DNA‐binding protein 43 (TDP‐43) is a highly conserved, ubiquitously expressed, DNA‐ and RNA‐binding protein (Buratti & Baralle, ; Ou, Wu, Harrich, Garcia‐Martinez, & Gaynor, ) which has recently emerged as possibly involved in the pathophysiology of several neurodegenerative conditions (Bigio, ; Nakashima‐Yasuda et al, ; Neumann et al, ; Schwab, Arai, Hasegawa, Yu, & McGeer, ) including AD (Amador‐Ortiz et al, ; Arai et al, ; Josephs et al, ; McAleese et al, : Uryu et al, ). TDP‐43 resides normally within the nucleus, however, under pathological conditions, its normal intracellular trafficking becomes altered, leading to both the formation of cytoplasmic inclusions and the loss of TDP‐43 nuclear localization and functions (Lee, Lee, & Trojanowski, ; Winton et al, ).…”

Section: Introductionmentioning

confidence: 99%

Essential role of hippocampal noradrenaline in the regulation of spatial working memory and TDP‐43 tissue pathology

Pintus

Riggi

Cannarozzo

et al. 2018

J of Comparative Neurology

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Extensive loss of noradrenaline-containing neurons and fibers is a nearly invariant feature of Alzheimer's Disease (AD). However, the exact noradrenergic contribution to cognitive and histopathological changes in AD is still unclear. Here, this issue was addressed following selective lesioning and intrahippocampal implantation of embryonic noradrenergic progenitors in developing rats. Starting from about 3 months and up to 12 months post-surgery, animals underwent behavioral tests to evaluate sensory-motor, as well as spatial learning and memory, followed by post-mortem morphometric analyses. At 9 months, Control, Lesioned and Lesion + Transplant animals exhibited equally efficient sensory-motor and reference memory performance. Interestingly, working memory abilities were seen severely impaired in Lesion-only rats and fully recovered in Transplanted rats, and appeared partly lost again 2 months after ablation of the implanted neuroblasts. Morphological analyses confirmed the almost total lesion-induced noradrenergic neuronal and terminal fiber loss, the near-normal reinnervation of the hippocampus promoted by the transplants, and its complete removal by the second lesion. Notably, the noradrenergic-rich transplants normalized also the nuclear expression of the transactive response DNA-binding protein 43 (TDP-43) in various hippocampal subregions, whose cytoplasmic (i.e., pathological) occurrence appeared dramatically increased as a result of the lesions. Thus, integrity of ascending noradrenergic inputs to the hippocampus may be required for the regulation of specific aspects of learning and memory and to prevent TDP-43 tissue pathology.

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TDP-43 Variants of Frontotemporal Lobar Degeneration

Cited by 22 publications

References 38 publications

Metabolism and mis-metabolism of the neuropathological signature protein TDP-43

Metabolism and mis-metabolism of the neuropathological signature protein TDP-43

TDP‐43 pathology in Alzheimer's disease, dementia with Lewy bodies and ageing

Essential role of hippocampal noradrenaline in the regulation of spatial working memory and TDP‐43 tissue pathology

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