Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: Evidence for clinico-pathologic subtypes

Takeuchi, Ryoko; Tada, Mari; Shiga, Atsushi; Toyoshima, Yasuko; Konno, Tetsuo; Sato, Tomoe; Nozaki, Hiroaki; Kato, Taisuke; Horie, Minoru; Shimizu, Hiroshi; Takebayashi, Hirohide; Onodera, Osamu; Nishizawa, Masatoyo; Kakita, Akiyoshi; Takahashi, Hitoshi

doi:10.1186/s40478-016-0335-2

Cited by 38 publications

(28 citation statements)

References 54 publications

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“…As recently reviewed, phosphorylation is one of the major posttranslational modifications of TDP‐43 that has been described to affect protein function both in healthy and disease conditions . Indeed, aberrant TDP‐43 phosphorylation at residues S409/410 is one of the major distinguishing features of TDP‐43 pathology . Regarding this issue, one important conclusion that can be drawn from our study is that there is no correlation between the abundance of TDP‐43 protein expression in different brain regions and the pathological S409/410 pTDP‐43 immunoreactivity.…”

Section: Discussionmentioning

confidence: 52%

Dysregulation of TDP‐43 intracellular localization and early onset ALS are associated with a TARDBP S375G variant

et al. 2018

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We investigated the Central Nervous System (CNS) and skeletal muscle tissue from A woman was clinically diagnosed with amyotrophic lateral sclerosis (ALS) at the age of 22. Neuropathologic evaluation showed upper and lower motor neuron loss, corticospinal tract degeneration and skeletal muscle denervation. Analysis of the patient's Deoxyribonucleic acid (DNA) revealed a AGT>GGT change resulting in an S375G substitution in the C‐terminal region of TDP‐43. This variant was previously reported as being benign. Considering the early onset and severity of the disease in this patient, we tested the effects of this genetic variant on TDP‐43 localization, pre‐mRNA splicing activity and toxicity, in parallel with the effects on known neighboring disease‐associated mutations. In cell lines, expressed in culture, S375G TDP‐43 appeared to be more significantly localized in the nucleus and to exert higher toxicity than wild‐type TDP‐43. Strikingly, a phosphomimic mutant at the same residue (S375E) showed a strong tendency to accumulate in the cytoplasm, especially under stress conditions, and molecular dynamics simulations suggest that phosphorylation of this residue can disrupt TDP‐43 intermolecular interactions. The results of the current study highlight the importance of phosphorylation and regulation of TDP‐43 nuclear‐cytoplasmic shuttling/redistribution, in relation to the pathogenetic mechanisms involved in different forms of ALS.

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Section: Discussionmentioning

confidence: 52%

Dysregulation of TDP‐43 intracellular localization and early onset ALS are associated with a TARDBP S375G variant

et al. 2018

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“…We do not believe this is the case, since only small number of dendrites have pTDP-43, and of these, only 4% also have poly-GR aggregations. Current classifications of ALS are based on TDP-43 neuropathology, and based either on morphology [6, 37, 48], or anatomy [6]. It has already been shown that occasionally TDP-43 surrounds perinuclear poly-GA aggregations [36] and there are perinuclear poly-GR and poly-PA aggregations in spinal cord that co-localized with pTDP-43 [16].…”

Section: Discussionmentioning

confidence: 99%

Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis

et al. 2017

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Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models. We quantitatively studied and compared DPRs, nuclear pore proteins and C9orf72 protein in clinically-related and clinically-unrelated regions of the central nervous system, and compared them to phosphorylated TDP-43 (pTDP-43), the hallmark protein of ALS. Of the five DPRs, only poly-GR was significantly abundant in clinically-related areas compared to unrelated areas (p<0.001), and formed dendritic-like aggregates in the motor cortex that co-localized with pTDP-43 (p<0.0001). While most poly-GR dendritic inclusions were pTDP-43-positive, only 4% of pTDP-43 dendritic inclusions were poly-GR-positive. Staining for arginine-containing poly-GR and poly-PR in nuclei of neurons produced signals that were not specific to C9 ALS. We could not detect significant differences of nuclear markers RanGap, Lamin B1, and Importin β1 in C9 ALS, although we observed subtle nuclear changes in ALS, both C9 and non-C9, compared to control. The C9orf72 protein itself was diffusely expressed in cytoplasm of large neurons and glia, and nearly 50% reduced, in both clinically-related frontal cortex and unrelated occipital cortex, but not in cerebellum. In summary, sense-encoded poly-GR DPR was unique, and localized to neurites and pTDP43 in motor regions of C9 ALS CNS. This is consistent with new emerging ideas about TDP-43 functions in dendrites.

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“…Based on the morphology and distribution of cortical TDP-43 pathology, FTLD cases are routinely classified into one of four pathological subtypes (FTLD-TDP Type A-D) [ 21 , 27 ], with Types A and B the most commonly identified in the ~20% of FTLD cases with ALS (FTLD-ALS) [ 8 , 17 , 22 , 27 ]. Although TDP-43 pathology is identified in the frontal cortices of ~70% of ALS cases without FTLD [ 9 ], these cases are not routinely subtyped according to the FTLD classification scheme, with a novel TDP-43 classification scheme recently proposed for ALS [ 29 ]. Given the wide acceptance of the FTLD-ALS continuum theory, it is not clear why cortical TDP-43 pathology would be classified according to two separate schemes, particularly since cortical TDP-43 pathology identified in Alzheimer’s disease cases (AD) are classified as per in FTLD [ 4 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Distinct TDP-43 inclusion morphologies in frontotemporal lobar degeneration with and without amyotrophic lateral sclerosis

Tan

Yang

Kim

et al. 2017

acta neuropathol commun

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The identification of the TAR DNA-binding protein 43 (TDP-43) as the ubiquitinated cytoplasmic inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) confirmed that these two diseases share similar mechanisms, likely to be linked to the abnormal hyperphosphorylation, ubiquitination and cleavage of pathological TDP-43. Importantly however, a quantitative analysis of TDP-43 inclusions in predilection cortical regions of FTLD, FTLD-ALS and ALS cases has not been undertaken. The present study set out to assess this and demonstrates that distinct TDP-43 inclusion morphologies exist in the anterior cingulate cortex, but not the motor cortex of FTLD and FTLD-ALS. Specifically, in the anterior cingulate cortex of FTLD cases, significant rounded TDP-43 inclusions and rare circumferential TDP-43 inclusions were identified. In contrast, FTLD-ALS cases revealed significant circumferential TDP-43 inclusions and rare rounded TDP-43 inclusions in the anterior cingulate cortex. Distinct TDP-43 inclusion morphologies in the anterior cingulate cortex of FTLD and FTLD-ALS may be linked to heterogeneity in the ubiquitination of pathological TDP-43 inclusions, with the present study providing evidence to suggest the involvement of distinct pathomechanisms in these two overlapping clinical syndromes.

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Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: Evidence for clinico-pathologic subtypes

Cited by 38 publications

References 54 publications

Dysregulation of TDP‐43 intracellular localization and early onset ALS are associated with a TARDBP S375G variant

Dysregulation of TDP‐43 intracellular localization and early onset ALS are associated with a TARDBP S375G variant

Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis

Distinct TDP-43 inclusion morphologies in frontotemporal lobar degeneration with and without amyotrophic lateral sclerosis

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