This report describes amyotrophic lateral sclerosis 10 (ALS10), which is a subtype of amyotrophic lateral sclerosis; ALS10 exhibits autosomal dominant inheritance. The human gene implicated in this disease is TARDBP (also known as TDP-43), which encodes a multi-functional DNA/RNA-binding protein involved in multiple levels of RNA processing including transcription, splicing, transport, and translation. There are two high-scoring fly orthologs: TBPH, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated; and CG7804, for which RNAi targeting constructs and alleles caused by insertional mutagenesis have been generated, but have not yet been analyzed in the context of an ALS10 model.
Multiple UAS constructs of the human Hsap\TARDBP gene have been introduced into flies, including wild-type TARDBP and genes carrying mutational lesions implicated in ALS10. Transgenic expression of both wild type and mutant human TARDBP recapitulate many of the key phenotypes of ALS10, including neurotoxicity, protein aggregation, locomotor defects, sleep disruption, and decreased lifespan. Phenotypic assays using the human gene have allowed characterization of genetic interactions with both fly genes and with other transgenically expressed human genes. Heterologous rescue (functional complementation) of some phenotypes of Dmel\TBPH null mutants has been demonstrated.
Variant(s) implicated in human disease tested (as transgenic human gene, TARDBP): the D169G, N267S, G287S, G294A, G298S, A315T, Q331K, M337V, Q343R, G348C, and A382T variant forms of the human gene have been introduced into flies.
For loss-of-function mutations in the Dmel\TBPH gene, observed phenotypes include aspects similar to the human disease, including neurodegeneration, locomotor defects, and reduced lifespan. Physical interactions of the Dmel\TBPH protein product have been described; see below and in the TBPH gene report. Phenotypic assays using the human and fly genes have allowed characterization of genetic interactions and screening of therapeutic drug candidates.
[updated Dec. 2018 by FlyBase; FBrf0222196]