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Defective proteostasis in induced pluripotent stem cell models of frontotemporal lobar degeneration

Mahali, Sidhartha, Martinez, Rita, King, Melvin, Verbeck, Anthony, Harari, Oscar, Benitez, Bruno A., Horie, Kanta, Sato, Chihiro, Temple, Sally, Karch, Celeste M.·2022·Translational Psychiatry
DOI 10.1038/s41398-022-02274-5PMC PMC9734180
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Abstract

Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the accumulation of protein, which can be toxic to cells and tissue. In a subset of frontotemporal lobar degeneration with tau pathology (FTLD-tau) cases, pathogenic mutations in the microtubule-associated protein tau (MAPT) gene are sufficient to cause tau accumulation and neurodegeneration. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. Here, we show that molecular networks associated with lysosomal biogenesis and autophagic function are disrupted in brains from FTLD-tau patients carrying a MAPT p.R406W mutation. We then used human induced pluripotent stem cell (iPSC)-derived neurons and 3D cerebral organoids from patients carrying the MAPT p.R406W mutation and CRISPR/Cas9, corrected controls to evaluate proteostasis. MAPT p.R406W was sufficient to induce morphological and functional deficits in the lysosomal pathway in iPSC-neurons. These phenotypes were reversed upon correction of the mutant allele with CRISPR/Cas9. Treatment with mTOR inhibitors led to tau degradation specifically in MAPT p.R406W neurons. Together, our findings suggest that MAPT p.R406W is sufficient to cause impaired lysosomal function, which may contribute to disease pathogenesis and serve as a cellular phenotype for drug screening.

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Metadata

Authors
Mahali, S., Martinez, R., King, M., Verbeck, A., Harari, O., Benitez, B. A., Horie, K., Sato, C., Temple, S., & Karch, C. M.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-12-10
Volume
12
Issue
1
ISSN
2158-3188
DOI
10.1038/s41398-022-02274-5
PMC
PMC9734180
Cited by
33
References
15
Language
en
Licence
Funders
U.S. Department of Health & Human Services | National Institutes of Health (R01 AG056293, R56 NS110890, RF1 AG053303)

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