More than 140 mutations in the SOD1 gene cause aggregation of the affected protein in familial forms of amyotrophic lateral sclerosis (fALS) which is a fatal progressive neurodegenerative disorder selectively affecting motor neurons. The causes of motor neuron death in ALS are poorly understood in general, but for fALS, aberrant oligomerization of SOD1 mutant proteins has been strongly concerned. Increasing evidences indicate that the interaction of amyloid aggregates with membranes is critical in the onset and progression of amyloid diseases. In spite of gathering reports describing mechanisms of membrane permeabilization by aggregates in model membranes, studies focused at characterizing the events occurring in biological membranes are exceptional. To gain insight into possible mechanisms of cytotoxicity at the membrane level, we describe interaction of the fibrillation products of the wild type (WT) and two mutants (E100K, D125H) of SOD1 obtained under destabilizing conditions with mitochondrial membranes. Release of mitochondrial enzymes, malate dehydrogenase (MDH) and adenylate kinase (AK), upon exposure to SOD1 aggregates demonstrates that these aggregates could affect membrane integrity. This effect correlates with the surface hydrophobicity of oligomers and their tendency toward amyloid formation, with the most toxic oligomers having high hydrophobicity and increased amount of amyloid formation.
Keywords: Aggregation; Familial amyotrophic lateral sclerosis; Membrane permeability; Mitochondria; Superoxide dismutase.
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