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Background: We aimed to gain new insights into the pathogenesis of sporadic ALS (sALS) through a comprehensive proteomic analysis. Methods: Protein profiles of the anterior and posterior horn in post-mortem spinal cord samples of 10 ALS patients and 10 controls were analysed using 2D-differential gel electrophoresis. The identified protein spots with statistically significant level changes and a spot ratio >2.0 were analysed by LC-MS/MS. Results: In the posterior horn only 3 proteins were differentially expressed. In the anterior horn, 16 proteins with increased levels and 2 proteins with decreased levels were identified in ALS compared to controls. The identified proteins were involved in mitochondrial metabolism, calcium homeostasis, protein metabolism, glutathione homeostasis, protein transport and snRNP assembly. The two proteins with decreased levels, ATP5D and calmodulin, were validated by Western blot and immunostaining. Immunohistochemical and immunofluorescent double staining of ATP5D and synaptophysin showed that the reduction of ATP5D was most pronounced at synapses. Conclusions: We speculate that mitochondrial dysfunction in synaptic clefts could play an important role in sALS pathogenesis. A similar approach revealed decreased calmodulin expression mainly in the neuronal body and dendrites of ALS patients. These findings contribute to a deeper understanding of the disease process underlying ALS. [ABSTRACT FROM AUTHOR]