TY - JOUR
T1 - Defective proteostasis in induced pluripotent stem cell models of frontotemporal lobar degeneration
AU - Mahali, Sidhartha
AU - Martinez, Rita
AU - King, Melvin
AU - Verbeck, Anthony
AU - Harari, Oscar
AU - Benitez, Bruno A.
AU - Horie, Kanta
AU - Sato, Chihiro
AU - Temple, Sally
AU - Karch, Celeste M.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85143700635&partnerID=8YFLogxK
U2 - 10.1038/s41398-022-02274-5
DO - 10.1038/s41398-022-02274-5
M3 - Article
C2 - 36494352
AN - SCOPUS:85143700635
SN - 2158-3188
VL - 12
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 508
ER -