Mitotic defects lead to neuronal aneuploidy and apoptosis in frontotemporal lobar degeneration caused by MAPT mutations
| Autor: | Christina M. Coughlan, Heidi J. Chial, Dennis W. Dickson, Julbert Caneus, Rosa Rademakers, Huntington Potter, Antoneta Granic |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Heterozygote Gene Dosage Aneuploidy Apoptosis Mice Transgenic tau Proteins Biology medicine.disease_cause 03 medical and health sciences mental disorders medicine Animals Humans Molecular Biology Mitosis Neurons Mutation Homozygote Chromosome Heterozygote advantage Cell Biology Frontotemporal lobar degeneration medicine.disease Spindle apparatus Mice Inbred C57BL 030104 developmental biology Human medicine Frontotemporal Lobar Degeneration |
| Zdroj: | Molecular biology of the cell |
| ISSN: | 1939-4586 1059-1524 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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