Integrative Genomic and Functional Analyses Reveal NINL as a Modulator of Tau Aggregation

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Proteostasis (protein homeostasis) dysfunction is central to neurodegenerative diseases like frontotemporal dementia (FTD) and Alzheimer's disease (AD).
• The specific genetic and molecular mechanisms underlying proteostasis disruption in these conditions are not fully understood.

Purpose of the Study:

• To identify components of the proteostasis network implicated in tauopathy.
• To investigate the role of specific genes and variants in the pathogenesis of FTD and AD.

Main Methods:

• Integration of human genetics, transcriptomics, and functional studies.
• Analysis of rare, damaging variants in proteostasis network genes.
• Differential gene expression analysis in mutant neurons and human brain tissue.
• Functional assessment of NINL (NINL) and its variants in cellular models.

Main Results:

• Identified 18 proteostasis network genes with 75 rare, damaging variants enriched in FTD and/or AD.
• These genes showed differential expression in MAPT mutant neurons and were dysregulated in FTD and AD brains.
• NINL (NINL) was consistently upregulated across all datasets and its overexpression reduced tau seeding and enhanced lysosomal activity.
• FTD-associated NINL (NINL) frameshift variants impaired Nlp expression and abolished protective effects.

Conclusions:

• A set of proteostasis genes with genetic and transcriptional links to neurodegeneration has been identified.
• NINL (NINL) is revealed as a novel regulator of tau aggregation, potentially acting as an adaptive response to proteotoxic stress.
• Specific NINL (NINL) variants found in FTD patients disrupt its protective function, highlighting its role in disease pathogenesis.