Abstract
ABSTRACTWe here investigated the effects of overexpressed superoxide dismutase (SOD)1 and amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants G93A and G147S in Neuro 2A (N2A) cell lines, and found a three-fold increase in lamellipodia either in cells cultured under differentiated or undifferentiated growth conditions. In undifferentiated N2A cells, SOD1 constructs promoted lamellipodial protrusions to similar extent as the overexpression of Rac1, and SOD1-mediated lamellipodia were prevented by coexpression of the N17 dominant-negative form of Rac1, or shRNA for a downstream effector of Rac1, the insulin receptor tyrosine kinase substrate p53 (IRSp53) or its binding partner LIN7. Moreover, no additive effect was measured by coexpression of the SOD1 constructs with Rac1, IRSp53 or LIN7. Collectively these data support a role for SOD1 in the regulation of Rac1-mediated lamellipodia pathway, a property fully retained by the two SOD1 mutants.
Highlights
Amyotrophic lateral sclerosis (ALS) is a devastating agerelated neurodegenerative disease characterised by a progressive loss of motor neurons of the central nervous system, leading to progressive muscle denervation and paralysis [1]
Cells cultured in undifferentiated growth conditions (15% foetal bovine serum (FBS)) for 48 hours after transfection were scored for the presence of lamellipodial protrusions by phalloidin staining of F-actin
Rac1 activity is mainly involved in the organisation of actin-based lamellipodial protrusions in all the cell types, with pivotal roles in neurons, where these structures are required for axon extension and guidance, formation of axon branches and synaptic structures [9]
Summary
Amyotrophic lateral sclerosis (ALS) is a devastating agerelated neurodegenerative disease characterised by a progressive loss of motor neurons of the central nervous system, leading to progressive muscle denervation and paralysis [1]. No effective therapy is available for ALS, and understanding the disease pathogenesis could help in developing effective treatments. Twenty percent of inherited ALS is caused by mutations in the gene encoding for superoxide dismutase 1 (SOD1), an ubiquitously expressed enzyme functioning in the clearance of potentially toxic superoxide radicals. The resulting mutant proteins have additional but still unclear functions that are toxic for motor neurons. Whereas damage to motor neurons is associated to the onset of ALS, damage to astrocytes and microglia severely accelerates disease progression [4,5,6]
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