The present invention provides methods and compositions for modulating polyamine pathway activity as a means for ameliorating neurodegenarative disorders. In particular, for ameliorating the symptoms or onset of amyotrophic lateral sclerosis (ALS) by modulating the gene and protein products involved the polyamine pathway, such as by inhibiting the enzyme, ornithine decarboxylase (ODC), involved in the synthesis of the polyamine, putrescine. Compositions and methods are disclosed for inhibiting the polyamine pathway producing lower polyamine levels resulting in a beneficial effect on ALS. This can be accomplished by using modulating agents such as analogs, or polyamine analogs, and antiproliferative drugs. In particular, the polyamine analog N(1),N(11)-diethylnorspermine (DENSPM) is disclosed as a useful modulating agent in the treatment of ALS. Screening assays for pharmacological agents that are capable of decreasing polyamine levels and/or reducing cell proliferation are also disclosed.