FTDP-17: An early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation

Sperfeld, Anne D.; Collatz, M.B.; Baier, Hartmut; Palmbach, Markus; Storch, Alexander; Schwarz, Johannes; Tatsch, Klaus; Reske, Sven N.; Joosse, Marijke; Heutink, Peter; Ludolph, Albert C.

doi:10.1002/1531-8249(199911)46:5<708::aid-ana5>3.0.co;2-k

Cited by 182 publications

(113 citation statements)

References 23 publications

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“…In addition, the P301S mutation shows a very early mean age of onset for FTD in man. 33 Compared with other tau Tg mouse models, the THYTau22 model has a rather early onset of tau pathology starting at 3 to 6 months (Table 3), especially for a heterozygous genotype. The variability among the individuals was very small.…”

Section: Discussionsupporting

confidence: 45%

Alzheimer's Disease-Like Tau Neuropathology Leads to Memory Deficits and Loss of Functional Synapses in a Novel Mutated Tau Transgenic Mouse without Any Motor Deficits

Schindowski

Bretteville

Leroy³

et al. 2006

The American Journal of Pathology

327

377

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Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2-promotor, displaying tau pathology in the absence of any motor dysfunction. THY-Tau22 shows hyperphosphorylation of tau on several Alzheimer's disease-relevant tau epitopes (AT8, AT100, AT180, AT270, 12E8, taupSer396, and AP422), neurofibrillary tangle-like inclusions (Gallyas and MC1-positive) with rare ghost tangles and PHF-like filaments, as well as mild astrogliosis. These mice also display deficits in hippocampal synaptic transmission and impaired behavior characterized by increased anxiety, delayed learning from 3 months, and reduced spatial memory at 10 months. There are no signs of motor deficits or changes in motor activity at any age investigated. This mouse model therefore displays the main features of tau pathology and several of the pathophysiological disturbances observed during neurofibrillary degeneration. This model will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits during pathogenic tau aggregation. Alzheimer's disease (AD) is the most common form of dementia in the elderly and is characterized neuropathologically by the presence of intracellular neurofibrillary tangles (NFTs) and senile plaques in the brain and by a major loss of synaptic connections. NFTs are neuronal inclusions of the microtubule-associated tau protein and are composed of aggregated phosphorylated tau. In AD, NFTs occur in the hippocampus, the entorhinal and polymodal association cortices, and in the basal forebrain. These brain areas are also severely affected by neuronal and synaptic loss. The loss of neurites, synapses, and neurons represent one of the reasons for the cognitive deficits and dementia of AD.

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Section: Discussionsupporting

confidence: 45%

Alzheimer's Disease-Like Tau Neuropathology Leads to Memory Deficits and Loss of Functional Synapses in a Novel Mutated Tau Transgenic Mouse without Any Motor Deficits

Schindowski

Bretteville

Leroy³

et al. 2006

The American Journal of Pathology

327

377

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“…The use of a plate reader for measuring FRET has certain disadvantages, and thus we created a facile, next-generation system to detect seeding activity with ultrahigh sensitivity and specificity. We engineered a monoclonal FRET biosensor HEK293T cell line to stably express the tau repeat domain (RD) with the disease-associated P301S mutation fused to either CFP or YFP (23,24), hereafter, referred to as "tau biosensor cells." This line was selected for its optimized RD-CFP/YFP expression levels and minimal background FRET signal.…”

Section: Resultsmentioning

confidence: 99%

Proteopathic tau seeding predicts tauopathy in vivo

Holmes

Furman

Mahan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

522

792

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Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼300 fM) and synuclein (∼300 pM) fibrils. This assay readily discriminates Alzheimer's disease vs. Huntington's disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.amyloid | neuropathology | dementia | aging P rotein aggregation characterizes many neurodegenerative disorders, including Alzheimer's disease (AD) and the related tauopathies. These disorders feature the accumulation of fibrillar deposits of the microtubule-associated protein tau with progressive deterioration of the central nervous system. Tau pathology and its associated brain atrophy do not appear randomly throughout the brain, but rather progress along distinct neural networks (1-5). This aspect suggests a role for transcellular spread of a pathogenic agent via neural connections. Our laboratory and others have previously hypothesized that tau aggregates-or seeds-serve as this agent of spread, transmitting the aggregated state from cell to cell via prion-like mechanisms (6-15).Mounting fundamental insights support this hypothesis. Tau seeds applied to the outside of cells bind the cell surface by attaching to heparan sulfate proteoglycans, triggering uptake by macropinocytosis (13). Upon internalization, tau seeds nucleate the fibrillization of endogenous tau monomer via templated conformational change, or seeding (8, 10). Tau seeding requires a critical unit of size for activity, as only particular species propagate the aggregated state (16). In vivo studies have described tau protein spreading from local sites to distant regions, presumably via transsynaptic movement (11,12,(17)(18)(19). Finally, our laboratory and another recently demonstrated that tau propagates discrete amyloid conformations through the brains of animals that give rise to unique neuropathologies (18,20).Despite this evidence, it remains unclear wheth...

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“…Concerning the tau gene MAPT missense mutations p.Gly272Val, p.Asn279Lys, p.Pro301Leu, p.Pro301Ser, p.Arg406Trp, p.Gly389Arg, p.Val337Met and p.Ser305Asn were found in the patients with frontotemporal dementia type of Parkinsonism [29][30][31][32][33][34][35][36][37]. The substitution mutation (rs63750072; p.Gln230Arg) found in our study exchanges uncharged polar amino acids for alkaline in MAPT gene.…”

Section: Discussionmentioning

confidence: 99%

Next Generation Sequencing Data Analysis Evaluation in Patients with Parkinsonism from a Genetically Isolated Population

Vodička

Vrtěl

Menšíková

et al. 2017

Genomics Comput Biol

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FTDP-17: An early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation

Cited by 182 publications

References 23 publications

Alzheimer's Disease-Like Tau Neuropathology Leads to Memory Deficits and Loss of Functional Synapses in a Novel Mutated Tau Transgenic Mouse without Any Motor Deficits

Alzheimer's Disease-Like Tau Neuropathology Leads to Memory Deficits and Loss of Functional Synapses in a Novel Mutated Tau Transgenic Mouse without Any Motor Deficits

Proteopathic tau seeding predicts tauopathy in vivo

Next Generation Sequencing Data Analysis Evaluation in Patients with Parkinsonism from a Genetically Isolated Population

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