ORIGINAL PAPER Dietary Supplementation with S-Adenosyl Methionine Delays the Onset of Motor Neuron Pathology in a Murine Model of Amyotrophic Lateral Sclerosis James Suchy Æ Sangmook Lee Æ Ambar Ahmed Æ Thomas B. Shea Received: 10 June 2009 / Accepted: 25 August 2009 / Published online: 16 September 2009 Ó Humana Press Inc. 2009 Abstract The full range of causative factors in Amyo- trophic lateral sclerosis (ALS) remains elusive, but oxida- tive stress is recognized as a contributing factor. Mutations in Cu/Zn superoxide dismutase 1 (SOD-1), associated with familial ALS, promote widespread oxidative damage. Mice-expressing G93A mutant human SOD-1 mice display multiple pathological changes characteristic of ALS and are therefore useful for therapeutic development. Dietary supplementation with S-adenosyl methionine (SAM) has provided multiple neuroprotective effects in mouse models of age-related cognitive pathology. We examined herein whether SAM supplementation could affect the course of motor neuron pathology in mice-expressing mutant human SOD-1. SAM delayed disease onset by 2–3 weeks. SAM also delayed hallmarks of neurodegeneration in these mice and in ALS, including preventing loss of motor neurons, and reducing gliosis, SOD-1 aggregation, protein carbon- ylation, and induction of antioxidant activity. SAM did not increase survival time. These preliminary findings, using a single concentration of SAM, suggest that SAM supple- mentation maybe useful as part of a comprehensive ther- apeutic approach for ALS. Keywords Amyotrophic lateral sclerosis Á Motor neuron Á Neuropathology Á S-Adenosyl methionine Á Nutritional supplement Á Transgenic mouse Introduction Amyotrophic lateral sclerosis (ALS) is an age-related dis- order characterized by a progressive loss of motor neurons, with eventual degeneration of muscles themselves, result- ing in paralysis and death. The onset and progression of ALS varies tremendously among affected individuals (Strong 2003). Aberrant function of Cu/Zn superoxide dismutase 1 (SOD-1) is associated with ALS (Julien and Mushynski 1998; Rosen et al. 1993; Strong 2003). More than 100 different mutations have been described that span all exons (Bruijn et al. 2004). Mutations in SOD-1 account for only 20% of the familial cases of ALS, which them- selves make up only 5–10% of the total cases, indicating that one or more additional factors is/are involved in the onset and/or progression of ALS. ALS may therefore rep- resent a complex disorder that can arise from several stages along the way (Rothstein 1996; Strong 2003). Transgenic mice expressing the G93A mutation of human SOD-1 undergo progressive decline in motor neuron function, typically originating in lower limbs and spreading to all limbs, commencing between 3 and 4 months of age and leading to death between 5 and 6 months of age (Gurney et al. 1994). These mice also display multiple biochemical and neurological pathological changes analo- gous to human ALS (Cozzolino et al. 2008; Hensley et al. 2006; Shibata 2001) and are therefore useful for therapeutic development (Turner and Talbot 2008). S-Adenosyl methionine (SAM), an intermediary in the ‘‘one-carbon’’ folate- and B12-dependent methionine cycle, is essential for methylation (which protects DNA and proteins), transsulfuration (which generates glutathi- one), and polyamine synthesis (essential for cell survival and growth) (Bottiglieri 2002; Lieber and Packer 2002; Lu 2000). The amount of SAM required to support these James Suchy and Sangmook Lee contributed equally to this work. J. Suchy Á S. Lee Á A. Ahmed Á T. B. Shea (&) Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA e-mail: Thomas_Shea@uml.edu Neuromol Med (2010) 12:86–97 DOI 10.1007/s12017-009-8089-7