Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Neumann, Manuela; Sampathu, Deepak M.; Kwong, Linda K.; Truax, Adam C.; Micsenyi, Matthew C.; Chou, Thomas T.; Bruce, Jennifer; Schuck, Theresa; Grossman, Murray; Clark, Christopher M.; McCluskey, Leo; Miller, Bruce L.; Masliah, Eliezer; Mackenzie, Ian R.; Feldman, Howard; Feiden, W.; Kretzschmar, Hans A.; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1126/science.1134108

Cited by 5,568 publications

(5,924 citation statements)

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“…Unfortunately, no biological samples were available from other members of the probandÕs family for genetic analysis; however, there is a very strong documented family history of dementia. Furthermore, the clinical presentation of both FTLD and ALS in the proband is consistent with the current hypothesis that FTLD and ALS represent two extremes of a clinicopathological spectrum of disease, TDP-43 proteinopathies [8].…”

Section: Resultssupporting

confidence: 87%

“…FTLD-U [6,7]. Recently, the transactive response (TAR) DNA-binding protein 43 (TDP-43) was identified as the major disease protein in UBIs that accumulate in the central nervous system (CNS) of patients with FTLD-U as well as in patients with sporadic and familial ALS [8], but not in the majority of patients with familial ALS (FALS) due to SOD-1 gene mutations [8][9][10][11][12]. These data provided compelling evidence that FTLD-U and ALS represent a clinicopathological spectrum of the same neurodegenerative disorder, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…TDP-43, encoded by the TARDBP gene on chromosome 1, is a highly conserved, ubiquitously expressed nuclear protein implicated in repression of gene transcription, inhibition of exon splicing and interactions with splicing factors and nuclear bodies [17,18]. Under physiological conditions, TDP-43 is predominately localized to the nucleus; however, pathological TDP-43 forms inclusions in neuronal perikarya and neurites, suggesting that the redistribution and sequestration of TDP-43 in the cytoplasm is a pathogenic mechanism [8]. Moreover, we have identified a specific bipartite nuclear localization signal (NLS) sequence in the amino terminal domain of TDP-43 that is required for nuclear targeting [19].…”

Section: Introductionmentioning

confidence: 99%

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A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

et al. 2008

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TAR DNA-binding protein-43 (TDP-43) is a highly conserved, ubiquitously expressed nuclear protein that was recently identified as the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Pathogenic TDP-43 gene (TARDBP) mutations have been identified in familial ALS kindreds, and here we report a TARDBP variant (A90V) in a FTLD/ALS patient with a family history of dementia. Significantly, A90V is located between the bipartite nuclear localization signal sequence of TDP-43 and the in vitro expression of TDP-43-A90V led to its sequestration with endogenous TDP-43 as insoluble cytoplasmic aggregates. Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

et al. 2008

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“…Diagnostic groups were enriched with CSF from patients with FTLD‐Plus syndromes that reflect high correlation with a specific neuropathology. Thus, the FTLD‐TDP group was enriched with FTLD patients with amyotrophic lateral sclerosis (FTLD‐ALS, n = 7), associated with TDP43 pathology 15. FTLD cases with tau neuropathology (FTLD‐Tau, n = 20) were selected based on autopsy ( n = 2), MAPT mutations ( n = 2),6 and familial history of autopsy confirmed FTLD‐Tau ( n = 1).…”

Section: Methodsmentioning

confidence: 99%

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Campo

Galimberti

Elias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveFrontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD‐Tau) or TDP43 (FTLD‐TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes.Methods YKL40, FABP4, MFG‐E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD‐TDP (n = 30), FTLD‐Tau (n = 20), AD (n = 30), DLB (n = 29), and nondemented controls (n = 29) obtained from two different centers. Models were validated in an independent CSF cohort (n = 188).Results YKL40 and catalase activity were increased in FTLD‐TDP cases compared to controls. YKL40 levels were also higher in FTLD‐TDP compared to FTLD‐Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG‐E8, tTau, and Aβ 42; 78% sensitivity and 83% specificity) and non‐FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD‐TDP from FTLD‐Tau (YKL40, MFGE‐8, βHexA together with βHexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity.InterpretationThis study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity > 80%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies.

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“…This pathological misfolding of proteins in AD,4 ALS,5, 6 Parkinson's Disease (PD),7 and Huntington's Disease (HD) 8 suggests that an approach to inhibit the production of toxic proteins within the cell may be an effective therapy. One such approach includes lowering levels of RNA to decrease protein translation using molecules such as antisense oligonucleotides (ASOs) or small interfering RNA (siRNA).…”

Section: Introductionmentioning

confidence: 99%

Protein production is an early biomarker for RNA‐targeted therapies

Self

Schoch

Alex

et al. 2018

Ann Clin Transl Neurol

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ObjectivesClinical trials for progressive neurodegenerative disorders such as Alzheimer's Disease and Amyotrophic Lateral Sclerosis have been hindered due to the absence of effective pharmacodynamics markers to assay target engagement. We tested whether measurements of new protein production would be a viable pharmacodynamics tool for RNA‐targeted therapies.MethodsTransgenic animal models expressing human proteins implicated in neurodegenerative disorders – microtubule‐associated protein tau (hTau) or superoxide dismutase‐1 (hSOD1) – were treated with antisense oligonucleotides (ASOs) delivered to the central nervous system to target these human mRNA transcripts. Simultaneously, animals were administered 13C6‐leucine via drinking water to measure new protein synthesis after ASO treatment. Measures of new protein synthesis and protein concentration were assayed at designated time points after ASO treatment using targeted proteomics.Results ASO treatment lowered hTau mRNA and protein production (measured by 13C6‐leucine‐labeled hTau protein) earlier than total hTau protein concentration in transgenic mouse cortex. In the CSF of hSOD1 transgenic rats, ASO treatment lowered newly generated hSOD1 protein driven by decreases in newly synthesized hSOD1 protein, not overall protein concentration, 30 days after treatment. At later time points, decreases in newly generated protein were still observed after mRNA lowering reached a steady state after ASO treatment.InterpretationMeasures of newly generated protein show earlier pharmacodynamics changes for RNA‐lowering therapeutics compared with total protein concentration. Early in ASO treatment, decreases in newly generated protein are driven by changes in newly synthesized protein. Measuring new protein production in CSF may be a promising early pharmacodynamics marker for RNA‐targeted therapeutics.

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Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Cited by 5,568 publications

References 24 publications

A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Protein production is an early biomarker for RNA‐targeted therapies

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