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Mutations in superoxide dismutase-1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most common mutation, D90A, disease can develop in both homozygous and, more rarely, in heterozygous individuals with unexplained differences in clinical presentation. There is mounting evidence that prion-like spread of SOD1 aggregation is the primary cause of the disease. Two different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic mouse models of ALS. Strain A is formed by most mutants including hSOD1G85R and hSOD1WT, whereas hSOD1D90A transgenic mice form a distinct strain B in addition to A. To explore the effects of aggregate strain propensities when hSOD1 variants are coexpressed, we generated digenic hSOD1G85R/WT and hSOD1G85R/D90A mice. Coexpression of hSOD1WT considerably shortened the lifespan of hSOD1G85R mice to the extent expected from the neurotoxicities of the variants alone. In contrast, coexpression of hSOD1D90A had a minimal effect on survival, far smaller than expected. Moreover, time from onset to the end stage was markedly prolonged in the hSOD1G85R/D90A mice. Aggregation of hSOD1 developed concomitantly with motor neuron disease, and the aggregates contained large amounts of both coexpressed variants in both digenic models. Our findings suggest that hSOD1WT has high a capacity to coaggregate with mutants and enhance neurotoxicity. Such interactions may be restricted by differences in strain propensities, which may contribute to the primarily recessive inheritance associated with the hSOD1D90A mutation.

Introduction: The motor system is selectively vulnerable to mutations in the ubiquitously expressed aggregation-prone enzyme superoxide dismutase-1 (SOD1).

Results: Autophagy clears aggregates, and factors involved in the process were analyzed in multiple areas of the CNS from human control subjects (n = 10) and amyotrophic lateral sclerosis (ALS) patients (n = 18) with or without SOD1 mutations. In control subjects, the key regulatory protein Beclin 1 and downstream factors were remarkably scarce in spinal motor areas. In ALS patients, there was evidence of moderate autophagy activation and also dysregulation. These changes were largest in SOD1 mutation carriers. To explore consequences of low autophagy capacity, effects of a heterozygous deletion of Beclin 1 were examined in ALS mouse models expressing mutant SOD1s. This caused earlier SOD1 aggregation, onset of symptoms, motor neuron loss, and a markedly shortened survival. In contrast, the levels of soluble misfolded SOD1 species were reduced.

Conclusions: The findings suggest that an inherent low autophagy capacity might cause the vulnerability of the motor system, and that SOD1 aggregation plays a crucial role in the pathogenesis.

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease. The pathogenesis of the disease is poorly understood, but intracellular copper dyshomeostasis has been implicated as a key process in the disease. We recently observed that metallothioneins (MTs) are an excellent target for the modification of copper dyshomeostasis in a mouse model of ALS (SOD1(G93A)). Here, we offer a therapeutic strategy designed to increase the level of endogenous MTs. The upregulation of endogenous MTs by dexamethasone, a synthetic glucocorticoid, significantly improved the disease course and rescued motor neurons in SOD1(G93A) mice, even if the induction was initiated when peak body weight had decreased by 10 %. Neuroprotection was associated with the normalization of copper dyshomeostasis, as well as with decreased levels of SOD1(G93A) aggregates. Importantly, these benefits were clearly mediated in a MT-dependent manner, as dexamethasone did not provide any protection when endogenous MTs were abolished from SOD1(G93A) mice. In conclusion, the upregulation of endogenous MTs represents a promising strategy for the treatment of ALS linked to mutant SOD1.

Over 170 mutations in superoxide dismutase-1 (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). The properties of SOD1 mutants differ considerably including copper-binding abilities. Nevertheless, they cause the same disease phenotype, suggesting a common neurotoxic pathway. We have previously reported that copper homeostasis is disturbed in spinal cords of SOD1(G93A) mice. However, it is unknown whether copper dyshomeostasis is induced by other SOD1 mutants. Using the additional mouse strains SOD1(G127insTGGG), SOD1(G85R), and SOD1(D90A), which express SOD1 mutants with different copper-binding abilities, we show that copper dyshomeostasis is common to SOD1 mutants. The SOD1 mutants shifted the copper trafficking systems toward copper accumulation in spinal cords of the mice. Copper contents bound to the SOD1 active site varied considerably between SOD1 mutants. Still, copper bound to other ligands in the spinal cord were markedly increased in all. Zinc was also increased, whereas there were no changes in magnesium, calcium, aluminum, manganese and iron. Further support for a role of copper dyshomeostasis in ALS was gained from results of pharmacological intervention. Ammonium tetrathiomolybdate (TTM), a copper chelating agent, prolonged survival and slowed the disease progression of SOD1(G93A) mice, even when the treatment was started after the disease onset. TTM markedly attenuated pathology, including the loss of motor neurons and axons, and atrophy of skeletal muscles. Additionally, TTM decreased amounts of SOD1 aggregates. We propose that pharmacological agents that are capable of modulating copper dyshomeostasis, such as TTM, might be beneficial for the treatment of ALS caused by SOD1 mutations.

Mutation in superoxide diamutasel (SOD1) is a cause of hereditary form of amyotrophic lateral sclerosis (ALS). Novel acquired toxicity (gain-of-function) is believed to play a crucial role. We propose that the nature of mutant SOD1 toxicity is disruption of intracellular Cu homeostasis. We provide evidences that copper transporters and chaperons are geared to accumulate Cu ion in the cells, and its excretion is downregulated with mutant SOD1 ("intracellular copper dysregulation" theory). Intracellular Cu modification using a Cu chelator and/or metallothionein resulted in a favorable outcome in an experimental study with a rodent model for hereditary form of ALS.