This report describes amyotrophic lateral sclerosis 1 (ALS1), which is a subtype of amyotrophic lateral sclerosis. The human gene implicated in this disease is SOD1, which is a Cu-Zn superoxide dismutase. Most cases of SOD1-related familial ALS follow autosomal dominant inheritance; rare cases of autosomal recessive inheritance have been reported. There is one high-scoring fly ortholog of SOD1, Sod1, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human gene Hsap\SOD1 have been introduced into flies, including wild-type SOD1 and genes carrying mutational lesions implicated in ALS1; phenotypes similar to aspects of the human disease are observed. Heterologous rescue (functional complementation) of some phenotypes of Dmel\Sod1 null mutants has been demonstrated.
Variant(s) implicated in human disease tested (as transgenic human gene, SOD1): the A4V, G37R, G41D, G85R, G93A, G93C, and I114T variant forms of the human gene have been introduced into flies. Variants implicated in ALS1 have been introduced into the endogenous Dmel\Sod1 locus via homologous recombination. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G36R in the fly Sod1 gene [corresponds to G37R (G38R) in the human SOD1 gene]; H47R in the fly Sod1 gene [corresponds to [H48R (H49R) in the human SOD1 gene]; H70Y in the fly Sod1 gene [corresponds to H71Y(H72Y) in the human SOD1 gene]; G84R in the fly Sod1 gene [corresponds to G85R (G86R) in the human SOD1 gene].
Animals homozygous for loss-of-function mutations in the Dmel\Sod1 gene (including alleles analogous to human variants that render the protein enzymatically inactive) exhibit phenotypes similar to the human disease, including neurodegeneration, locomotor deficits, and reduced lifespan. Physical interactions of the Dmel\Sod1 protein product have been described; see below and in the Sod1 gene report. Phenotypic assays using the fly gene have allowed characterization of genetic interactions.
[updated Jan. 2018 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from OMIM:105400, 2015.02.11]
[AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1](https://omim.org/entry/105400)
[DYNACTIN 1; DCTN1](https://omim.org/entry/601143)
[SUPEROXIDE DISMUTASE 1; SOD1](https://omim.org/entry/147450)
[NEUROFILAMENT PROTEIN, HEAVY POLYPEPTIDE; NEFH](https://omim.org/entry/162230)
The SOD1 gene encodes superoxide dismutase-1, a major cytoplasmic antioxidant enzyme that metabolizes superoxide radicals to molecular oxygen and hydrogen peroxide, thus providing a defense against oxygen toxicity (Niwa et al., 2007, pubmed:17666395). Soluble cytoplasmic SOD1 is a copper- and zinc-containing enzyme (Sherman et al., 1983, pubmed:6577438). [from OMIM:147450, 2015.02.12]
Dmel\Sod shares 57% identity and 67% similarity with human SOD1.
Ortholog of human SOD1 (1 Drosophila to 1 human).