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    Loss of NMNAT2 enzyme disrupts neuronal NAD+ levels, leading to APP processing errors and protein buildup. SARM1 protein knockdown rescues these deficits, highlighting a key pathway in neurodegeneration.

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    Area of Science:

    • Neuroscience
    • Cellular Metabolism
    • Neurodegenerative Diseases

    Background:

    • Metabolic dysfunction and proteinopathy are key features of neurodegenerative diseases.
    • The mechanistic link between these hallmarks is not well understood.

    Purpose of the Study:

    • To investigate the role of Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in neuronal metabolism and protein processing.
    • To elucidate the interplay between NAD+ homeostasis, amyloid precursor protein (APP) processing, and neurodegeneration.

    Main Methods:

    • Utilized NMNAT2 knockout (KO) and sterile alpha and TIR motif-containing protein 1 (SARM1) knockdown (KD) in cortical neurons.
    • Performed Seahorse metabolic flux analysis, redox profiling, and proteomic analysis.
    • Investigated APP C-terminal fragments (APP-CTFs) accumulation and signaling pathway activation.

    Main Results:

    • NMNAT2 loss caused APP-CTF accumulation and impaired neuronal metabolism, including deficits in glycolysis and mitochondrial respiration.
    • SARM1 KD restored APP-CTF levels and mitochondrial function in NMNAT2 KO neurons, while NAD+ supplementation had minimal effect.
    • Proteomic analysis revealed biphasic changes, including early JNK/MAPK signaling activation and late endoplasmic reticulum stress.

    Conclusions:

    • Neuronal NAD+ depletion, mediated by NMNAT2 loss, triggers SARM1-dependent proteostasis and redox imbalance, leading to impaired APP processing.
    • The NMNAT2-SARM1 pathway is a critical link between metabolic stress and proteinopathy in neurodegeneration.
    • SARM1 acts as a key mediator in neurodegenerative dysfunction.