SARM: From immune regulator to cell executioner

Area of Science:

• Molecular biology
• Immunology
• Neuroscience

Background:

• SARM is a conserved Toll/Il-1 Receptor (TIR) adaptor protein.
• Unlike other TIR adaptors, SARM modulates Toll-like receptor (TLR) signaling and innate immunity.
• SARM plays a critical role in neuronal cell death and axon degeneration.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying SARM-mediated axon degeneration.
• To investigate the enzymatic activity of SARM and its regulation.
• To explore the therapeutic potential of targeting SARM in neurodegenerative diseases.

Main Methods:

• Investigated SARM's interaction with TRIF and MyD88.
• Assessed SARM's role in innate immune responses and cell death pathways.
• Examined SARM's NADase activity in vitro and its regulation by NMNAT2.
• Studied SARM orthologues in C. elegans and Drosophila.

Main Results:

• SARM inhibits TLR signaling by interacting with TRIF and MyD88.
• SARM exhibits intrinsic NADase activity within its TIR domain, depleting NAD+.
• This NADase activity is crucial for SARM-mediated axon degeneration and is regulated by NMNAT2.
• SARM's functions are conserved across species and enriched in CNS neurons.

Conclusions:

• SARM is a key regulator of innate immunity and neuronal cell death.
• SARM's NADase activity is a critical mechanism for axon degeneration.
• Targeting SARM's enzymatic function offers a promising therapeutic strategy for neurodegenerative conditions like multiple sclerosis and motor neuron disease.