Intergenerational epigenetic inheritance mediated by MYS-2/MOF in the pathogenesis of Alzheimer's disease

Area of Science:

• Neuroscience
• Genetics
• Epigenetics

Background:

• Familial Alzheimer's disease (FAD) clustering is often attributed to autosomal-dominant inheritance, yet this accounts for a small fraction of cases.
• The role of epigenetic mechanisms in the intergenerational transmission of Alzheimer's disease (AD) pathogenesis remains underexplored.

Purpose of the Study:

• To investigate epigenetic memory as a potential mechanism contributing to intergenerational Alzheimer's disease pathogenesis.
• To explore the role of the mys-2 gene and H4K16 acetylation in AD occurrence and inheritance.

Main Methods:

• Utilized *Caenorhabditis elegans* (*C. elegans*) as an *in vivo* model system.
• Investigated the function of mys-2, encoding a MYST acetyltransferase involved in H4K16 acetylation.
• Analyzed the impact of mys-2 dysfunction on phenotypic traits and gene expression patterns in parent and progeny generations.
• Examined the upstream regulatory pathway involving ROS/CDK-5/ATM.

Main Results:

• Mys-2 dysfunction in parent *C. elegans* led to phenotypic improvements that were inherited by progeny via epigenetic memory.
• Inherited epigenetic changes resulted in consistent H4K16ac levels and altered gene expression in AD-related pathways.
• The ROS/CDK-5/ATM pathway was identified as an upstream activator of MYS-2.
• Evidence suggests intergenerational inheritance of MYS-2/MOF via epigenetic mechanisms in *C. elegans* and a mammalian AD model.

Conclusions:

• Epigenetic memory involving MYS-2/MOF can mediate intergenerational inheritance of AD-related traits.
• This mechanism offers a novel perspective on the etiology and inheritance patterns of familial Alzheimer's disease.
• Findings in *C. elegans* and mammalian cells highlight a conserved epigenetic pathway relevant to AD pathogenesis.