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Molecular genetic basis of familial ALS
T Siddique1, D Nijhawan, A Hentati
1Department of Neurology, Northwestern University Medical School, Chicago, IL 60611, USA.
Abstract:
Familial amytrophic lateral sclerosis (FALS) is transmitted in a mendelian fashion as an autosomal dominant (DFALS) or an autosomal recessive (RFALS) trait. Both DFALS and RFALS are genetically heterogeneous. Fifteen percent of DFALS families have mutations in the gene for Cu, Zn superoxide dismutase (SOD1) which is coded on chromosome 21. The locus for one form of RFALS maps to chromosome 2q33. Forty-six mutations in the SOD1 gene have been reported in DFALS families. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Transgenic mice overexpressing mutated SOD1 protein develop an ALS-like disease which suggests that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Several possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed.
Insights
Familial amyotrophic lateral sclerosis (ALS) can be inherited. Mutations in the Cu, Zn superoxide dismutase (SOD1) gene are linked to familial ALS, suggesting a toxic gain of function in motor neuron degeneration.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Familial amyotrophic lateral sclerosis (FALS) exhibits Mendelian inheritance patterns, including autosomal dominant (DFALS) and autosomal recessive (RFALS) forms.
- Both DFALS and RFALS are genetically heterogeneous, indicating multiple underlying genetic causes.
- Mutations in the Cu, Zn superoxide dismutase (SOD1) gene account for 15% of DFALS cases and are located on chromosome 21.
Purpose of the Study:
- To investigate the genetic basis of FALS.
- To explore the role of SOD1 mutations in the pathogenesis of FALS.
- To discuss potential mechanisms of neurotoxicity associated with mutated SOD1.
Main Methods:
- Genetic analysis of FALS families to identify mutations.
- Characterization of SOD1 gene mutations and their effects on protein activity and stability.
- Utilizing transgenic mouse models overexpressing mutated SOD1 to study disease mechanisms.
Main Results:
- Forty-six distinct SOD1 mutations have been identified in DFALS families.
- These mutations typically lead to reduced SOD1 activity and protein half-life.
- Transgenic mice expressing mutated SOD1 develop an ALS-like phenotype.
Conclusions:
- Motor neuron degeneration in DFALS is likely caused by a novel toxic function acquired by mutated SOD1, not solely by decreased SOD1 activity.
- The gain of a toxic function by mutated SOD1 is a key mechanism in DFALS pathogenesis.
- Further research is needed to elucidate the specific mechanisms of SOD1-mediated neurotoxicity.