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dc.contributor.authorBritti, Elena
dc.contributor.authorRos Salvador, Joaquim
dc.contributor.authorEsteras, Noemi
dc.contributor.authorAbramov, Andey Y.
dc.description.abstractAggregation or phosphorylation of the microtubule-associated protein tau is the pathological hallmark in a number of diseases termed tauopathies, which include the most common neurodegenerative disorder, Alzheimer’s disease; or frontotemporal dementia, linked to mutations in the gene MAPT encoding tau. Although misfolded tau has strong familial and histopathological (as in intracellular tangles) association with neurodegenerative disorders, the cellular mechanism of tau-induced pathology remains to be controversial. Here we studied the effect of tau on the cytosolic and mitochondrial calcium homeostasis using primary cortical cultures treated with the protein and iPSC-derived neurons bearing the 10 + 16 MAPT mutation linked to frontotemporal dementia. We found that incubation of the primary cortical co-cultures of neurons and astrocytes with tau induced spontaneous Ca2+ oscillations in the neurons, which were also observed in iPSC-neurons with the 10 + 16 MAPT mutation. Importantly, tau inhibited mitochondrial calcium efflux via the mitochondrial Na+/Ca2+ exchanger (NCLX) in both neurons and astrocytes. This inhibition led to mitochondrial depolarisation in response to physiological and pathological calcium stimuli and made these cells vulnerable to calcium-induced caspase 3 activation and cell death. Thus, inhibition of the mitochondrial NCLX in neurons with misfolded or mutated tau can be involved in the mechanism of neurodegeneration.ca_ES
dc.description.sponsorshipEB was supported with an EMBO short-term fellowship (number 7834) for the development of this project. The work was supported by EPSRC grant EP/R024898/1.ca_ES
dc.relation.isformatofVersió postprint del document publicat a
dc.relation.ispartofCell Calcium, 2020, vol. 86, 102150ca_ES
dc.rightscc-by-nc-nd (c) Elsevier, 2020ca_ES
dc.subjectMitochondrial calciumca_ES
dc.subjectFrontotemporal dementiaca_ES
dc.subjectMitochondrial effluxca_ES
dc.titleTau inhibits mitochondrial calcium efflux and makes neurons vulnerable to calciuminduced cell deathca_ES

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cc-by-nc-nd (c) Elsevier, 2020
Except where otherwise noted, this item's license is described as cc-by-nc-nd (c) Elsevier, 2020