Defective proteostasis in induced pluripotent stem cell models of frontotemporal lobar degeneration.
Sidhartha MahaliRita MartinezMelvin KingAnthony VerbeckOscar HarariBruno A BenitezKanta HorieChihiro SatoSally TempleCeleste M KarchPublished in: Translational psychiatry (2022)
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.
Keyphrases
- crispr cas
- cerebrospinal fluid
- stem cells
- end stage renal disease
- spinal cord
- newly diagnosed
- ejection fraction
- chronic kidney disease
- genome editing
- traumatic brain injury
- endothelial cells
- prognostic factors
- induced pluripotent stem cells
- induced apoptosis
- gene expression
- poor prognosis
- emergency department
- high glucose
- drug induced
- patient reported outcomes
- mesenchymal stem cells
- brain injury
- dna methylation
- patient reported
- endoplasmic reticulum stress
- replacement therapy
- smoking cessation
- endoplasmic reticulum
- wild type