Interplay between RNA m⁶A modification and transglutaminase 2 inhibitor effects on mitophagy dysfunction in...

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Alzheimer's disease (AD) is characterized by amyloid-β aggregation, tau hyperphosphorylation, and mitochondrial dysfunction.
• Defective mitophagy, a cellular process for removing damaged mitochondria, is implicated in AD pathogenesis.
• RNA N6-methyladenosine (m6A) modification and transglutaminase 2 (TG2) are emerging as key regulators of mitochondrial quality control in AD.

Purpose of the Study:

• To investigate the roles of m6A modification and TG2 in regulating mitophagy and neuronal damage in Alzheimer's disease.
• To explore the potential of dual m6A-TG2 targeting as a therapeutic strategy for AD.

Main Methods:

• Investigated the impact of METTL3/METTL14 downregulation and fat mass and obesity-associated protein upregulation on m6A methylation and mitophagy.
• Examined the effects of TG2 overexpression on mitochondrial stress, protein crosslinking, and mitophagy.
• Assessed the efficacy of pharmacological modulators, including TG2 inhibitors (Z-DON) and m6A enhancers (METTL3 overexpression), in preclinical AD models.

Main Results:

• Downregulation of m6A methylation impairs mitophagy, increases reactive oxygen species, and leads to synaptic loss in AD.
• TG2 overexpression exacerbates mitochondrial stress, disrupts mitochondrial dynamics, and suppresses mitophagy.
• Pharmacological interventions targeting m6A and TG2 restored mitophagic flux and mitigated AD pathology in preclinical models.

Conclusions:

• Dysregulation of m6A modification and TG2 contributes significantly to neuronal damage in Alzheimer's disease.
• Dual targeting of m6A and TG2 pathways presents a novel and promising disease-modifying therapeutic approach for AD.
• Restoring mitophagic flux through combined m6A and TG2 modulation offers a potential strategy to combat AD progression.