Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells

Molecular Neurodegeneration

Guojun Bu¹  Takahisa Kanekiyo¹  Zbigniew K. Wszolek³  Dennis W. Dickson¹  Owen A. Ross¹  Rosa Rademakers¹  Pawel Tacik³  Audrey J. Strongosky³  Kotaro Ogaki¹  Hirotaka J. Okano²  Yuan Fu¹  Mary D. Davis¹  Yuka Atagi¹  Melissa E. Murray¹  Chia-Chen Liu¹  Jing Zhao¹  Melissa C. Wren¹ 

[1] Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville 32224, FL, USA;Division of Regenerative Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Tokyo 105-8461, Minato-ku, Japan;Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville 32224, FL, USA

关键词: Tau;    PPND;    Neural stem cells;    N279K;    iPSCs;    FTDP-17;   

Others  :  1225450
DOI  :  10.1186/s13024-015-0042-7

 received in 2015-08-17, accepted in 2015-09-07,  发布年份 2015

【 摘 要 】

Background

Pallido-ponto-nigral degeneration (PPND), a major subtype of frontotemporal dementia with parkinsonism related to chromosome 17 (FTDP-17), is a progressive and terminal neurodegenerative disease caused by c.837 T > G mutation in the MAPT gene encoding microtubule-associated protein tau (rs63750756; N279K). This MAPT mutation induces alternative splicing of exon 10, resulting in a modification of microtubule-binding region of tau. Although mutations in the MAPT gene have been linked to multiple tauopathies including Alzheimer’s disease, frontotemporal dementia and progressive supranuclear palsy, knowledge regarding how tau N279K mutation causes PPND/FTDP-17 is limited.

Results

We investigated the underlying disease mechanism associated with the N279K tau mutation using PPND/FTDP-17 patient-derived induced pluripotent stem cells (iPSCs) and autopsy brains. In iPSC-derived neural stem cells (NSCs), the N279K tau mutation induced an increased ratio of 4-repeat to 3-repeat tau and accumulation of stress granules indicating elevated cellular stress. More significant, NSCs derived from patients with the N279K tau mutation displayed impaired endocytic trafficking as evidenced by accumulation of endosomes and exosomes, and a reduction of lysosomes. Since there were no significant differences in cellular stress and distribution of subcellular organelles between control and N279K skin fibroblasts, N279K-related vesicle trafficking defects are likely specific to the neuronal lineage. Consistently, the levels of intracellular/luminal vesicle and exosome marker flotillin-1 were significantly increased in frontal and temporal cortices of PPND/FTDP-17 patients with the N279K tau mutation, events that were not seen in the occipital cortex which is the most spared cortical region in the patients.

Conclusion

Together, our results demonstrate that alterations of intracellular vesicle trafficking in NSCs/neurons likely contribute to neurodegeneration as an important disease mechanism underlying the N279K tau mutation in PPND/FTDP-17.

【 授权许可】

   
2015 Wren et al.

【 图 表 】

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