期刊
JOURNAL OF CELL SCIENCE
卷 129, 期 10, 页码 2003-2015出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.180745
关键词
Alzheimer's disease; Neurodegenerative disease; Functional genomics; Polarity signaling; Risk gene; PARD6A
类别
资金
- Academy of Finland (Suomen Akatemia) [218081, 263762, 125274]
- Brain and Mind doctoral program
- Integrative Life Science doctoral programs
- University of Helsinki funds
- Finnish Cultural Foundation (Suomen Kulttuurirahasto)
- VTR of Kuopio University Hospital (Kuopion Yliopistollinen Sairaala) [V16001]
- Sigrid Juselius Foundation (Sigrid Juseliuksen Saatio)
- Strategic Funding of the University of Eastern Finland (Ita-Suomen yliopisto)
- Strategic Funding of the University of Eastern Finland (UEF-Brain)
- Academy of Finland (AKA) [125274, 263762, 125274, 218081, 263762, 218081] Funding Source: Academy of Finland (AKA)
One of the defining pathological features of Alzheimer's disease is the intraneuronal accumulation of tau (also known as MAPT) protein. Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of Alzheimer's disease patients. Tau pathology might spread from cell to cell through a mechanism involving secretion and uptake. Here, we developed an assay to follow cellular release and uptake of tau dimers. Individual silencing of ten common late-onset Alzheimer's disease risk genes in HEK293T cells expressing the tau reporters suggested that FRMD4A is functionally linked to tau secretion. FRMD4A depletion by using RNA interference (RNAi) reduced and overexpression increased tau secretion. The activity of cytohesins, interactors of FRMD4A and guanine-nucleotide-exchange factors of Arf6, was necessary for FRMD4A-induced tau secretion. Increased Arf6 and cell polarity signaling through Par6 and atypical protein kinase C. (aPKC.) stimulated tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, regulates tau secretion by activating cytohesin-Arf6 signaling. We conclude that genetic risk factors of Alzheimer's disease might modulate disease progression by altering tau secretion.
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