Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains

Josephs, Keith A.; Murray, Melissa E.; Tosakulwong, Nirubol; Weigand, Stephen D.; Serie, Amanda M.; Perkerson, Ralph B.; Matchett, Billie J.; Jack, Clifford R.; Knopman, David S.; Petersen, Ronald C.; Parisi, Joseph E.; Petrucelli, Leonard; Baker, Matthew; Rademakers, Rosa; Whitwell, Jennifer L.; Dickson, Dennis W.

doi:10.1007/s00401-018-1951-7

Cited by 75 publications

(121 citation statements)

References 54 publications

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“…Recent study also suggested distinct TDP-43 types present in non-FTD brains, typical TDP-43 αtype and newly characterized β-type 65 . TDP-43 α-type is the typical form conventionally observed in temporal, frontal and brainstem regions.…”

Section: Discussionmentioning

confidence: 87%

The TMEM106B rs1990621 protective variant is also associated with increased neuronal proportion

Li¹,

Farias²,

Dube³

et al. 2019

Preprint

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Background: In previous studies, we observed decreased neuronal and increased astrocyte proportions in AD cases in parietal brain cortex by using a deconvolution method for bulk RNAseq. These findings suggested that genetic risk factors associated with AD etiology have a specific effect in the cellular composition of AD brains. The goal of this study is to investigate if there are genetic determinants for brain cell compositions. Methods:Using cell type composition inferred from transcriptome as a disease status proxy, we performed cell type association analysis to identify novel loci related to cellular population changes in disease cohort. We imputed and merged genotyping data from seven studies in total of 1,669 samples and derived major CNS cell type proportions from cortical RNAseq data. We also inferred RNA transcript integrity number (TIN) to account for RNA quality variances. The model we performed in the analysis was: normalized neuronal proportion ~ SNP + Age + Gender + PC1 + PC2 + median TIN.Results: A variant rs1990621 located in the TMEM106B gene region was significantly associated with neuronal proportion (p=6.40×10 -07 ) and replicated in an independent dataset. The association became more significant as we combined both discovery and replication datasets in multi-tissue meta-analysis (p=9.42×10 -09 ) and joint analysis (p=7.66×10 -10 ). This variant is in high LD with rs1990622 (r2 = 0.98) which was previously identified as a protective variant in FTD cohorts. Further analyses indicated that this variant is associated with increased neuronal proportion in participants with neurodegenerative disorders, not only in AD cohort but also in cognitive normal elderly cohort. However, this effect was not observed in a younger schizophrenia cohort with a mean age of death < 65. The second most significant loci for neuron 3 proportion was APOE, which suggested that using neuronal proportion as an informative endophenotype could help identify loci associated with neurodegeneration. Conclusion:This result suggested a common pathway involving TMEM106B shared by aging groups in the present or absence of neurodegenerative pathology may contribute to cognitive preservation and neuronal protection.

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Section: Discussionmentioning

confidence: 87%

The TMEM106B rs1990621 protective variant is also associated with increased neuronal proportion

Li¹,

Farias²,

Dube³

et al. 2019

Preprint

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show abstract

“…In addition, in most cases, the lesion type was perivascular [29]. TDP-43 associated with NFT known as TDP-43 type β [37] was the least common type of lesion observed. There was no significant difference in the final clinical diagnoses rendered before death or in the Mini-Mental State Examination [38] or Clinical Dementia Rating Scale sum of boxes [39] scores at the last examination before death.…”

Section: Resultsmentioning

confidence: 95%

“…This may suggest that symptomatic PART may be linked to TDP-43 extending beyond limbic regions. Given our recent report of two types of TDP-43, type α and type β, and that type α is characterized by higher TDP-43 stages [37], it is possible that TDP-43 in symptomatic PART is different from TDP-43 in asymptomatic definite PART.…”

Section: Discussionmentioning

confidence: 99%

Brain atrophy in primary age‐related tauopathy is linked to transactive response DNA‐binding protein of 43 kDa

Josephs

Murray

Tosakulwong

et al. 2019

Alzheimer's & Dementia

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Introduction: Primary age-related tauopathy (PART) is characterized by the presence of neurofibrillary tangles and absent-minimal β-amyloid deposition. Transactive response DNAbinding protein of 43 kDa (TDP-43), a third protein, has recently garnished a lot of attention in Alzheimer's disease where it is associated with memory loss and amygdala and hippocampal atrophy. We aimed to determine whether TDP-43 is associated with brain atrophy in PART. Methods: We assessed the frequency of TDP-43 in PART and performed voxel-level analysis in SPM12, as well as region-of-interest analysis using linear regression modeling, controlling for variables of interest, to assess for associations between TDP-43 and brain atrophy. Results: Of 116 PART cases, 31 (26.7%) had TDP-43. The presence of TDP-43 was associated with significantly greater amygdala, hippocampal, and anterior temporal atrophy in both the region-of-interest and the voxel level analyses.

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“…The heterogeneity of TDP-43 phenotypes in FTLD is well studied. 4,5,17 Abnormal TDP-43 structures are typically classified into neuronal cytoplasmic inclusions, neuronal preinclusions, neuronal intranuclear inclusions, and dystrophic neurites and the distribution of and presence of these TDP-43 features has been used to subtype FTLD and AD cases. [18][19][20] Consistent brain regions are affected by FTLD and AD and can be more readily assessed for TDP-43 pathology.…”

Section: Discussionmentioning

confidence: 99%

Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex

Salapa

Hutchinson

Popescu

et al. 2020

Ann Clin Transl Neurol

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Objective: Neurodegeneration is thought to be the primary cause of neurological disability in multiple sclerosis (MS). Dysfunctional RNA-binding proteins (RBPs) including their mislocalization from nucleus to cytoplasm, stress granule formation, and altered RNA metabolism have been found to underlie neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia. Yet, little is known about the role of dysfunctional RBPs in the pathogenesis of neurodegeneration in MS. As a follow-up to our seminal finding of altered RBP function in a single case of MS, we posited that there would be evidence of RBP dysfunction in cortical neurons in MS. Methods: Cortical neurons from 12 MS and six control cases were analyzed by immunohistochemistry for heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and TAR-DNA-binding protein-43 (TDP-43). Seven distinct neuronal phenotypes were identified based on the nucleocytoplasmic staining of these RBPs. Statistical analyses were performed by analyzing each phenotype in relation to MS versus controls. Results: Analyses revealed a continuum of hnRNP A1 and TDP-43 nucleocytoplasmic staining was found in cortical neurons, from neurons with entirely nuclear staining with little cytoplasmic staining in contrast to those with complete nuclear depletion of RBPs concurrent with robust cytoplasmic staining. The neuronal phenotypes that showed the most nucleocytoplasmic mislocalization of hnRNP A1 and TDP-43 statistically distinguished MS from control cases (P < 0.01, P < 0.001, respectively). Interpretation: The discovery of hnRNP A1 and TDP-43 nucleocytoplasmic mislocalization in neurons in MS brain demonstrate that dysfunctional RBPs may play a role in neurodegeneration in MS, as they do in other neurological diseases.

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Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains

Cited by 75 publications

References 54 publications

The TMEM106B rs1990621 protective variant is also associated with increased neuronal proportion

The TMEM106B rs1990621 protective variant is also associated with increased neuronal proportion

Brain atrophy in primary age‐related tauopathy is linked to transactive response DNA‐binding protein of 43 kDa

Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex

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