The role of SIRT1 deacetylase in neuromuscular aging and amyotrophic lateral sclerosis

SIRT1 deacetylase functions in a variety of cells and tissues to mitigate age- and disease-induced damages. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor units, and specifically alpha-motor neurons, with advancing age and during the progression of amyotrophic lateral sclerosis (ALS). Here, we show that SIRT1 expression decreases in the spinal cord of wild type mice with advancing age. Using mouse models that overexpress or inactivate SIRT1 in motor neurons, we discovered that SIRT1 prevents age-related degeneration of motor neurons' presynaptic sites at neuromuscular junctions (NMJs). We also found that increasing SIRT1 in motor neurons delays degeneration of presynaptic sites at NMJs and extends the lifespan of SOD1G93A mice. Thus, SIRT1 has a similar effect on aging and ALS-affected motor neurons, two conditions in which a remarkable number of transcripts are similarly altered in the spinal cord. These include genes involved in inflammatory and immune responses and genes with known function at synapses. These findings show that SIRT1 functions to mitigate pathological changes induced by aging and ALS, two conditions with a surprising degree of overlap in the spinal cord. Overall design: Eight replicates spinal cords from mice aged 18-24 months, eight replicates of spinal cords from mice aged 3-4 months, 3 replicates of spinal cords from ALS symptomatic mice aged 5-6 months and 3 replicates of spinal cords from wt controls aged 5-6 months.

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Herskovits AZ, Hunter TA, Maxwell N, Pereira K, Whittaker CA, Valdez G, Guarente LP