Minute quantities of misfolded mutant superoxide dismutase‐1 cause amyotrophic lateral sclerosis

Abstract

Mutant forms of superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS) by an unknown noxious mechanism. Using an antibody against a novel epitope in the G127insTGGG mutation, mutant SOD1 was studied for the first time in spinal cord and brain of an ALS patient. The level was below 0.5% of the SOD1 level in controls. In corresponding transgenic mice the content of mutant SOD1 was also low, although it was enriched in spinal cord and brain compared with other tissues. In the mice the misfolded mutant SOD1 aggregated rapidly and 20% occurred in steady state as detergent-soluble protoaggregates. The misfolded SOD1 and the protoaggregates form, from birth until death, a potentially noxious burden that may induce the motor neuron injury. Detergent-resistant aggregates, as well as inclusions of mutant SOD1 in motor neurons and astrocytes, accumulated in spinal cord ventral horns of the patient and mice with terminal disease. The inclusions and aggregates may serve as terminal markers of long-term assault by misfolded SOD1 and protoaggregates.

Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice

“…Interestingly, when WT SOD1 is coexpressed in the L126Z transgenic animal, a heterodimer of the truncated and full-length protein is observed. Detergent-resistant nonnative dimer has been observed in the spinal cord of the transgenic mouse expressing a similar truncated mutant SOD1, G127insTGGG (G127X), and in the spinal cord ventral horns of a patient carrying the G127X mutation (34,36). Although cytotoxicity of the disulfide-linked SOD1 multimers needs to be investigated, disulfide-bonded nonnative dimer apparently is sufficient to induce more extensive protein aggregation.…”

In-cell NMR reveals potential precursor of toxic species from SOD1 fALS mutants

“…One hundred and sixty-five unique fALS-linked SOD1 mutations have been identified so far, which are scattered throughout SOD1 amino acid sequence (ALSod, the Amyotrophic Lateral Sclerosis Online Genetic Database, 2012, http://alsod.iop.kcl.ac.uk/). The pathogenic role of SOD1 in ALS has been linked to the formation of protein aggregates rich in SOD1, observed both in the spinal cords of patients with ALS [17][18][19] and of transgenic mice expressing human forms of the protein [20][21][22][23] , with accumulation primarily in the late stages of the disease. The precursors of these protein aggregates are believed to be soluble oligomeric intermediates of the SOD1 aggregation process.…”

Metal-free superoxide dismutase forms soluble oligomers under physiological conditions: A possible general mechanism for familial ALS

“…Over 114 different variants of human copper-zinc superoxide dismutase (Cu 2 Zn 2 SOD1) have been linked to the neurodegenerative disease familial ALS (FALS) by a gain-of-function mechanism (4-6). Although the exact cellular sites and mechanisms of toxicity are unknown, aberrant SOD1 protein oligomerization has been strongly implicated in disease causation (7,8). Several recent publications have presented compelling evidence that abnormal disulfide cross-linking of ALS-mutant SOD1 plays a role in this oligomerization, and disulfide-linked SOD1 multimers have been detected in neural tissues of SOD1-ALS transgenic mice that are presumed to be components of higher-molecular-weight species or intermediates in their formation (7, 9-11).…”