Mitotic defects lead to neuronal aneuploidy and apoptosis in frontotemporal lobar degeneration caused by MAPT mutations
Year: 2017
Type: article
Abstract: Mutant Tau (MAPT) can lead to frontotemporal lobar degeneration (FTLD). Previous studies associated MAPT mutations and altered function with aneuploidy and chromosome instability in human lymphocytes and in Drosophila development. Here we examine whether FTLD-causing mutations in human MAPT induce aneuploidy and apoptosis in the mammalian brain. First, aneuploidy was found in brain cells from MAPT mutant transgenic mice expressing FTLD mutant human MAPT. Then brain neurons from mice homozygous or heterozygous for the Tau (Mapt) null allele were found to exhibit increasing levels of aneuploidy with decreasing Tau gene dosage. To determine whether aneuploidy leads to neurodegeneration in FTLD, we measured aneuploidy and apoptosis in brain cells from patients with MAPT mutations and identified both increased aneuploidy and apoptosis in the same brain neurons and glia. To determine whether there is a direct relationship between MAPT-induced aneuploidy and apoptosis, we expressed FTLD-causing mutant forms of MAPT in karyotypically normal human cells and found that they cause aneuploidy and mitotic spindle defects that then result in apoptosis. Collectively, our findings reveal a neurodegenerative pathway in FTLD-MAPT in which neurons and glia exhibit mitotic spindle abnormalities, chromosome mis-segregation, and aneuploidy, which then lead to apoptosis.
Source: Molecular Biology of the Cell
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Michael J. Fox Foundation for Parkinson's Research, Mayo Clinic, Alzheimer's Association, Arizona Department of Health Services, National Institute for Health and Care Research, Newcastle University, Arizona Biomedical Research Commission, NIHR Newcastle Biomedical Research Centre, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: G1052080286, G1576660248, G1999460359, G2387188009, G250893170, G2898431357, G3250808129, G3251040009, G3521153818, G3540482749, G3687506083, G4193400840, G4791902628, G6030318873, G6125194395, Florida Alzheimer's Disease Research, Arizona Alzheimer's Disease Core Center, G7161884846, National Brain and Tissue Resource for Parkinson's Disease and Related Disorders, G7747731141, G7788227861, G7836467104, Abnormal Low Density Lipoprotein Receptor Localization and Function in AD, G837617365, G961669115, G989695202
OpenAlex ID: W2779633104