TDP-43 in Familial and Sporadic Frontotemporal Lobar Degeneration with Ubiquitin Inclusions

Cairns, Nigel J.; Neumann, Manuela; Bigio, Eileen H.; Holm, Ida E.; Troost, Dirk; Hatanpaa, Kimmo J.; Foong, Chan; White, Charles L.; Schneider, Julie A.; Kretzschmar, Hans A.; Carter, Deborah; Taylor‐Reinwald, Lisa; Paulsmeyer, Katherine; Strider, Jeffrey; Gitcho, Michael A.; Goate, Alison M.; Morris, John C.; Mishra, Manjari; Kwong, Linda K.; Stieber, Anna; Xu, Yan; Forman, Mark S.; Trojanowski, John Q.; Lee, Virginia M.‐Y.; Mackenzie, Ian R.

doi:10.2353/ajpath.2007.070182

Cited by 463 publications

(534 citation statements)

References 49 publications

(90 reference statements)

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“…Neuronal and glial inclusions containing TDP-43 have been reported in FTLD-U, amyotrophic lateral sclerosis (ALS) and some AD cases [3,33]. It should be noted that LB pathology has been seen in families with progranulin mutations, a common cause of hereditary FTLD-U [8,22,26]. However, the clinical course of the S167 individual had no resemblance to FTLD-U.…”

Section: Discussionmentioning

confidence: 99%

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

et al. 2008

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Individuals with familial Parkinson's disease (PD) due to a monogenic defect can show considerable clinical and neuropathological variability. To identify factors underlying this variability, histopathological analysis was performed in two clinically different A53T α-synuclein heterozygotes from Family H, a multigenerational α-synuclein A53T kindred. To determine whether additional genetic factors could contribute to phenotypic variability, Family H and another multigenerational A53T kindred were analyzed for parkin polymorphisms. We identified a previously described variant in parkin exon 4 associated with increased PD risk (S167N). The two A53T heterozygotes had markedly different neuropathology and different parkin genotypes: A N167 homozygote had early onset rapidly progressive disease, early dementia, myoclonus and sleep disorder, while a S167 homozygote had late onset, slowly progressive disease and late dementia. Both had brainstem, cortical, and intraneuritic Lewy bodies (LB). The N167 individual had widespread cortical neurofibrillary degeneration, while the S167 individual had only medial temporal lobe neurofibrillary degeneration. The N167 individual had severe neuronal loss in CA2 associated with Lewy neurites (LN), while the S167 individual had severe neuronal loss in CA1 associated with TDP-43 immunoreactive neuronal inclusions. These findings implicate TDP-43 in the pathology of familial PD and suggest that parkin may act as a modifier of the A53T α-synuclein phenotype of familial PD. Furthermore, they suggest a mechanism by which a rare genetic variant that is associated with a minor increase of PD risk in the heterozygous state may, in the homozygous state, exacerbate a disease phenotype associated with a highly penetrant dominant allele.

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Section: Discussionmentioning

confidence: 99%

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

et al. 2008

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“…In addition to SOD1, TAR DNA binding protein (TDP-43) has been identified as a major component of cytoplasmic inclusions in sALS, SOD1-negative fALS and ALS with dementia; as well as the most common pathological subtype of frontotemporal dementia (FTD) with ubiquitinated inclusions (Arai et al 2006;Cairns et al 2007;Davidson et al 2007;Mackenzie et al 2010;Neumann et al 2006Neumann et al , 2007. However, aggregate formation pathways and final structures are likely different between SOD1 and TDP-43 (Farrawell et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Addition of exogenous SOD1 aggregates causes TDP-43 mislocalisation and aggregation

Zeineddine

Farrawell

Lambert-Smith

et al. 2017

Cell Stress and Chaperones

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ALS is characterised by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology throughout the nervous system, resulting in paralysis and death generally within a few years after diagnosis. The aberrant release and uptake of toxic proteins including SOD1 and TDP-43 and their subsequent propagation, accumulation and deposition in motor neurons may explain such a pattern of pathology. Previous work has suggested that the internalization of aggregates triggers stress granule formation. Given the close association of stress granules and TDP-43, we wondered whether internalisation of SOD1 aggregates stimulated TDP-43 cytosolic aggregate structures. Addition of recombinant mutant G93A SOD1 aggregates to NSC-34 cells was found to trigger a rapid shift of TDP-43 to the cytoplasm where it was still accumulated after 48 h. In addition, SOD1 aggregates also triggered cleavage of TDP-43 into fragments including a 25 kDa fragment. Collectively, this study suggests a role for protein aggregate uptake in TDP-43 pathology.

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“…Functional loss of 50% of the GRN protein in these cases causes neurodegeneration as a result of haploinsufficiency Cruts et al, 2006]. Interestingly, the DNA binding protein TDP-43 has been shown to be a component of the ubiquitinated inclusions of sporadic and familial FTLD-U and sporadic cases of MND [Neumann et al, 2006Cairns et al, 2007a].…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia

et al. 2008

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Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6-2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.

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TDP-43 in Familial and Sporadic Frontotemporal Lobar Degeneration with Ubiquitin Inclusions

Cited by 463 publications

References 49 publications

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

Addition of exogenous SOD1 aggregates causes TDP-43 mislocalisation and aggregation

Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia

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