New consensus research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 (SOD1) gene mutations: Inclusions containing SOD1 in neurons and astrocytes

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. Approximately 5-10% of ALS is familial. Superoxide dismutase 1 (SOD1) gene mutations are shown to be associated with about 20% of familial ALS (FALS) patients. The neuronal Lewy-body-like hyaline inclusion (LBHI) and astrocytic hyaline inclusion (Ast-HI) are morphological hallmarks of certain SOD1-linked FALS patients with SOD1 gene mutant and transgenic mice expressing human SOD1 with G85R mutation. From the detailed immunohistochemical analyses, the essential common protein of both inclusions is SOD1. Ultrastructurally, both inclusions consist of granule-coated fibrils 15-25 nm in diameter. Based on the immuno-electron microscopical finding that these abnormal granule-coated fibrils are positive for SOD1, the formation (or aggregation) of the abnormal fibrils containing SOD1 would be essential evidence in diseases caused by various SOD1 mutations. The granule-coated fibrils are also modified by advanced glycation end products (AGEs). The AGEs themselves are insoluble molecules with direct toxic effects on cells. AGE formation of SOD1 composing the granule-coated fibrils (probable AGE-modified mutant SOD1) may amplify their aggregation and produce a more marked toxicity.

Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro

“…5 A and B). The dimensions of the fibrils, the association of the fibrils with amorphous granular aggregates, and the bumpy surface of the fibrils resemble the description of in vivo SOD aggregates (9,27,28). These in vitro studies suggest that decreased stability of fALS SOD mutants is correlated with an increased propensity of these proteins to form aggregates and that in vitro SOD aggregates resemble aggregates found in vivo.…”

“…In fALS, inclusions (i.e., protein aggregates) that are intensely immunopositive for SOD are observed in motor neurons and astrocytes (9). There is evidence that the inclusions are initially composed mainly of granular material and later form randomly oriented 15-to 25-nm granule-coated fibrils (9). Aggregate formation is reduced, and cell viability is increased when mutant SOD is coexpressed with protein-folding chaperones in cell culture, suggesting that aggregation and cytotoxicity are related (12).…”

“…In such disorders, which include, for example, prion diseases, Ig light chain disorders, and transthyretin amyloidoses, naturally occurring proteins are altered or mutated, and the variant proteins misfold to form aggregates (11). In fALS, inclusions (i.e., protein aggregates) that are intensely immunopositive for SOD are observed in motor neurons and astrocytes (9). There is evidence that the inclusions are initially composed mainly of granular material and later form randomly oriented 15-to 25-nm granule-coated fibrils (9).…”

Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS

“…Amyloid is a type of aggregate structure formed by many disease-associated proteins, and perhaps by all proteins, often under destabilizing conditions (4). Although there has been some controversy concerning the amyloid-like nature of large insoluble aggregates in mutant SOD1 mice models of ALS, amyloid aggregates are not observed in ALS patients (5)(6)(7). Here, we characterize the formation of small, soluble, nonamyloid aggregates by mutant SOD1.…”

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…These observations are all consistent with cell-to-cell spread of misfolded proteins and subsequent templating of this conformation could underlie the spread of pathology, but does not rule out other possibilities. Familial forms of ALS (fALS) due to mutations in superoxide dismutase 1 (SOD1) [70,71], fused in sarcoma (FUS) [72,73], and TAR DNA-binding protein 43 (TDP-43) [74] are now widely described. These proteins accumulate in aggregates observed upon pathological examination of motor neurons, but have not been as extensively studied for potential prion-like mechanisms.…”