Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• Neurological diseases (NDs) like Alzheimer's (AD) and multiple sclerosis (MS) pose significant health and economic burdens.
• Genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with ND risk, but most are in noncoding regions, complicating functional studies.
• A major challenge is understanding the cell-type-specific roles of noncoding genetic variants in neurological disease pathogenesis.

Purpose of the Study:

• To pinpoint causal genes at 10 loci associated with Alzheimer's (AD) and multiple sclerosis (MS) risk.
• To leverage induced pluripotent stem cell (iPSC)-based models and functional genomics to overcome limitations in studying noncoding genetic variants.
• To identify novel genes and pathways involved in the pathophysiology of AD and MS.

Main Methods:

• Generation of neural progenitors, neurons, astrocytes, and microglia from iPSCs.
• Integration of RNA-sequencing, H3K27ac ChIP-sequencing, and Promoter Capture Hi-C.
• Comparison of iPSC-derived cells with primary human brain cells for physiological relevance.
• CRISPR interference (CRISPRi) screening in iPSC-derived microglia-like cells (iMGLs) targeting AD and MS risk SNPs.

Main Results:

• iPSC-derived cell types exhibited characteristic gene signatures and enhancer patterns, with iMGLs showing high similarity to primary microglia.
• Enrichment of AD and MS risk SNPs was observed in cell type-specific enhancers, particularly in microglia.
• Functional screening identified novel AD and MS risk genes, including MAF and ELMO1, with ELMO1 characterized as a new MS risk gene involved in microglial homeostasis.

Conclusions:

• The combined approach of iPSC models and functional genomics effectively identified previously uncharacterized risk genes for AD and MS.
• These findings highlight the role of neuroimmune pathways in disease pathophysiology by linking genetic risk variants to specific genes.
• Further research is ongoing to elucidate the functional impact of identified genes, such as MAF and ELMO1, on microglial function and neuronal/astrocyte interactions.