Tau protein mutation P364S in two sisters: clinical course and neuropathology with emphasis on new, composite neuronal tau inclusions

Popović, Mara; Fabjan, Andrej; Mraz, Jerica; Magdič, Jožef; Glavač, Damjan; Zupan, Andrej; Novak, Mateja Drolec; Bresjanac, Mara

doi:10.1007/s00401-014-1293-z

Cited by 7 publications

(6 citation statements)

References 4 publications

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“…MAPT mutations have been associated with pure FTD [16] and with FTD with parkinsonism and/or MND [7, 9, 11, 17], but also with progressive sopranuclear paralysis and Alzheimer disease [18, 19]. …”

Section: Discussionmentioning

confidence: 99%

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Role of MAPT in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients

et al. 2018

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The aim of our study was to evaluate the role of mutations in the MAPT gene in patients with pure amyotrophic lateral sclerosis (ALS). A cohort of 120 ALS patients, both sporadic and familial, without cognitive impairment was analyzed by next-generation sequencing with a multiple-gene panel comprising 23 genes, including MAPT, known to be associated with ALS and frontotemporal dementia. The presence of the C9orf72 expansion was also investigated. Twelve patients had mutations in the SOD1, TARDBP, MATR3, and FUS genes, while 10 patients carried the C9orf72 expansion. One female patient was found to carry the D348G mutation in MAPT, previously reported in an Italian family with lower motor neuron disease. Our patient presented both upper and lower motor neuron signs, early development of dyspnea, resting and kinetic tremor, and a slow disease course (> 11 years). The present case further broadens the clinical phenotype associated with MAPT mutations and suggests that, although rarely, MAPT mutations can cause ALS and, therefore, should be analyzed in ALS patients, especially in those with early breathing difficulties and long-lasting disease.

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Section: Discussionmentioning

confidence: 99%

“…Another association study by Fang et al [12] confirmed these findings and reported a higher incidence of breathing difficulties in sALS patients carrying specific MAPT genotypes. Moreover, in some studies, MAPT mutations have been reported to be associated with MND, although always in association with FTD [7, 9, 11]. …”

Section: Discussionmentioning

confidence: 99%

Role of MAPT in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients

et al. 2018

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“…MAPT P301L mutation leads to formation of predominantly Gallyas-negative pretangles and globular glial tauopathy composed of 4-repeat (4R) tau [2,17]. MAPT P364S mutation leads to a formation of composite neuronal tau inclusions (CNTI) constituted of both 3R and 4R tau [45]. MAPT L266V mutation leads to PiD phenotype [29].…”

Section: Soluble Picalm Protein Is Reduced and Autophagy Activity Is mentioning

confidence: 99%

Picalm reduction exacerbates tau pathology in a murine tauopathy model

et al. 2020

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Genome-wide association studies (GWAS) have identified PICALM as one of the most significant susceptibility loci for late-onset Alzheimer's disease (AD) after APOE and BIN1. PICALM is a clathrin-adaptor protein and plays critical roles in clathrin-mediated endocytosis and in autophagy. PICALM modulates brain amyloid ß (Aß) pathology and tau accumulation. We have previously reported that soluble PICALM protein level is reduced in correlation with abnormalities of autophagy markers in the affected brain areas of neurodegenerative diseases including AD, sporadic tauopathies and familial cases of frontotemporal lobar degeneration with tau-immunoreactive inclusions (FTLD-tau) with mutations in the microtubuleassociated protein tau (MAPT) gene. It remains unclarified whether in vivo PICALM reduction could either trigger or influence tau pathology progression in the brain. In this study, we confirmed a significant reduction of soluble PICALM protein and autophagy deficits in the post-mortem human brains of FTLD-tau-MAPT (P301L, S364S and L266V). We generated a novel transgenic mouse line named Tg30xPicalm+/− by crossing Tg30 tau transgenic mice with Picalm-haploinsufficient mice to test whether Picalm reduction may modulate tau pathology. While Picalm haploinsufficiency did not lead to any motor phenotype or detectable tau pathology in mouse brains, Tg30xPicalm+/− mice developed markedly more severe motor deficits than Tg30 by the age of 9 months. Tg30xPicalm+/− had significantly higher pathological tau levels in the brain, an increased density of neurofibrillary tangles compared to Tg30 mice and increased abnormalities of autophagy markers. Our results demonstrate that Picalm haploinsufficiency in transgenic Tg30 mice significantly aggravated tau pathologies and taumediated neurodegeneration, supporting a role for changes in Picalm expression as a risk/sensitizing factor for development of tau pathology and as a mechanism underlying the AD risk associated to PICALM.

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“…Affected sisters (IV.2 and IV.3) have been already described . Their mother (III.3 in Figure ) died at the age of 48 years, allegedly with dementia and displaying forward‐bent gait.…”

Section: Resultsmentioning

confidence: 95%

“…An in vitro experiment using recombinant P364S mutant tau revealed its increased aggregation rate and fibril formation relative to both wild‐type tau and representative MAPT P301L mutant tau . A peculiar composite neuronal tau inclusion (CNTI) was subsequently described in two female siblings of a Slovene family . We describe here the clinical presentation and neuropathological findings in four carriers of the P364S MAPT mutation of a family (Figure ).…”

Section: Introductionmentioning

confidence: 87%

Familial tauopathy with P364S MAPT mutation: clinical course, neuropathology and ultrastructure of neuronal tau inclusions

Štrafela

Pleško

Magdič

et al. 2018

Neuropathology Appl Neurobio

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(2018) Neuropathology and Applied Neurobiology 44, 550-562 Familial tauopathy with P364S MAPT mutation: clinical course, neuropathology and ultrastructure of neuronal tau inclusions Aims: This report presents the clinical course, neuropathology and ultrastructure of neuronal tau inclusions of four Slovene relatives with P364S MAPT mutation. Methods: The clinical history of three out of four P364S MAPT mutation carriers was taken. After formalin fixation, thorough sampling of the central nervous system was followed by paraffin embedding, H&E, Gallyas, Bielschowsky and immunostaining with AT8, anti-3R, anti-4R tau, anti-amyloid-b, anti-TDP43 and anti-alpha-synuclein antibodies. The distribution and density of different types of neuronal tau inclusions were semiquantitatively assessed. In addition, the ultrastructure of neuronal tau inclusions was analysed. Results: Macroscopic examination of the brains was unremarkable. Microscopically, neuronal tau inclusions of almost all known types were widespread and distributed fairly uniformly in all cases.Pick bodies and swollen neurones were found in only one family member. Mutant tau was composed of 3R and 4R isoforms, with a slight predominance of 3R tau. Composite neuronal tau inclusion (CNTI), found in all four relatives, was a hallmark of the P364S MAPT mutation. CNTI showed compartmental differences in H&E and Gallyas staining, tau isoforms immunolabelling and ultrastructure, displaying fuzzy fibrils in the core and paired twisted tubules at the periphery. Conclusions: P364S MAPT mutation is characterized clinically by a variable combination of frontotemporal dementia, parkinsonism and motor neurone disease of short duration, and neuropathologically by a widespread uniform distribution of all known neuronal tau inclusions in one family member. Two-compartment CNTI is a unique characteristic of the P364S MAPT mutation.

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Tau protein mutation P364S in two sisters: clinical course and neuropathology with emphasis on new, composite neuronal tau inclusions

Cited by 7 publications

References 4 publications

Role of <b><i>MAPT</i></b> in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients

Role of <b><i>MAPT</i></b> in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients

Picalm reduction exacerbates tau pathology in a murine tauopathy model

Familial tauopathy with P364S MAPT mutation: clinical course, neuropathology and ultrastructure of neuronal tau inclusions

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