Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Proteomics

Background:

• Tau protein dysfunction is implicated in over 20 neurodegenerative diseases, including frontotemporal dementia (FTD).
• The MAPT^V337M variant, a common FTD-associated mutation, leads to altered tau protein phosphorylation in human induced pluripotent stem cell (hiPSC)-derived models.
• Previous research has not fully explored the proteomic consequences of the MAPT^V337M variant in cortical organoids.

Purpose of the Study:

• To investigate the proteomic profile of hiPSC-derived cortical organoids carrying the MAPT^V337M mutation.
• To compare proteomic differences across wild-type, heterozygous, and homozygous MAPT^V337M organoid models at different developmental time points.
• To establish a model for studying genetic mutations linked to dementia.

Main Methods:

• Generation of isogenic hiPSC lines: MAPT^WT/WT (wild type), MAPT^WT/V337M (heterozygous), and MAPT^V337M/V337M (homozygous).
• Culture of single-rosette organoids for 90 and 180 days.
• Label-free quantitative proteomics (mass spectrometry) to identify and quantify proteins and post-translational modifications.

Main Results:

• Label-free quantitative analysis identified 2,988 proteins, with significant differences observed across genotypes and time points.
• Developmental time (180 days) had a greater impact on protein composition than the MAPT^V337M genotype.
• Increased tau peptides in the 4R tau domain were observed at 180 days; heterozygous organoids showed greater deviation from wild type than homozygous ones.
• Validation is underway for ANXA11, CLU, and TPPP3 protein level changes.

Conclusions:

• hiPSC-derived MAPT^V337M cortical organoids serve as a valuable model for exploring FTD-associated proteomic changes.
• The findings emphasize the critical role of temporal dynamics in organoid development and FTD pathogenesis.
• This study provides a framework for investigating other dementia-linked genetic mutations using organoid models.