1. G272V and P301L Mutations Induce Isoform Specific Tau Mislocalization to Dendritic Spines and Synaptic Dysfunctions in Cellular Models of 3R and 4R Tau Frontotemporal Dementia.
- Author
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Yu K, Yao KR, Aguinaga MA, Choquette JM, Liu C, Wang Y, and Liao D
- Subjects
- Animals, Rats, Male, Humans, Female, Synapses metabolism, Synapses pathology, Rats, Sprague-Dawley, Hippocampus metabolism, Hippocampus pathology, Cells, Cultured, tau Proteins metabolism, tau Proteins genetics, Frontotemporal Dementia genetics, Frontotemporal Dementia metabolism, Frontotemporal Dementia pathology, Dendritic Spines metabolism, Dendritic Spines pathology, Mutation, Protein Isoforms genetics, Protein Isoforms metabolism
- Abstract
Tau pathologies are detected in the brains of some of the most common neurodegenerative diseases including Alzheimer's disease (AD), Lewy body dementia (LBD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD). Tau proteins are expressed in six isoforms with either three or four microtubule-binding repeats (3R tau or 4R tau) due to alternative RNA splicing. AD, LBD, and CTE brains contain pathological deposits of both 3R and 4R tau. FTD patients can exhibit either 4R tau pathologies in most cases or 3R tau pathologies less commonly in Pick's disease, which is a subfamily of FTD. Here, we report the isoform-specific roles of tau in FTD. The P301L mutation, linked to familial 4R tau FTD, induces mislocalization of 4R tau to dendritic spines in primary hippocampal cultures that were prepared from neonatal rat pups of both sexes. Contrastingly, the G272V mutation, linked to familial Pick's disease, induces phosphorylation-dependent mislocalization of 3R tau but not 4R tau proteins to dendritic spines. The overexpression of G272V 3R tau but not 4R tau proteins leads to the reduction of dendritic spine density and suppression of mEPSCs in 5-week-old primary rat hippocampal cultures. The decrease in mEPSC amplitude caused by G272V 3R tau is dynamin-dependent whereas that caused by P301L 4R tau is dynamin-independent, indicating that the two tau isoforms activate different signaling pathways responsible for excitatory synaptic dysfunction. Our 3R and 4R tau studies here will shed new light on diverse mechanisms underlying FTD, AD, LBD, and CTE., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)
- Published
- 2024
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