TY - JOUR
T1 - Mitotic defects lead to neuronal aneuploidy and apoptosis in frontotemporal lobar degeneration caused by MAPT mutations
AU - Caneus, Julbert
AU - Granic, Antoneta
AU - Rademakers, Rosa
AU - Dickson, Dennis W.
AU - Coughlan, Christina M.
AU - Chial, Heidi J.
AU - Potter, Huntington
N1 - Funding Information:
The chromosome 16 BAC and MAPT expression vectors were kind gifts from Bruce Lamb and Chad Dickey, respectively. We also acknowledge with gratitude the contributions of neurologists, notably Neill Graff-Radford and Zbigniew Wszolek, in caring for the FTLD patients. Human brain tissue was obtained from the Mayo Clinic Brain Bank (Jacksonville, FL) and from the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City (Arizona), which is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30-AG19610, Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05–901, and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson’s Research. We appreciate the opportunity to present early results of this study at the 2013, 2014, and 2015 Alzheimer’s Association International Conferences. We also thank Joaquin Espinosa for his helpful suggestion to use Nutlin-3 to inhibit cell division in our experiments. This study was funded by National Institute of Aging grants (AG-025711 and AG-037942). A.G. is funded by the AGE Research Group to Avan A. Sayer (Institute of Neuroscience, Newcastle Institute for Ageing, National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle University, UK). We also acknowledge the generous support of donors.
Publisher Copyright:
© 2018 Caneus, Granic, et al.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
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U2 - 10.1091/mbc.E17-01-0031
DO - 10.1091/mbc.E17-01-0031
M3 - Article
C2 - 29282277
AN - SCOPUS:85042711295
VL - 29
SP - 575
EP - 586
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
SN - 1059-1524
IS - 5
ER -