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 cocoon, for which RNAi targeting constructs and alleles caused by insertional mutagenesis have been generated, but have not 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]
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 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS10](https://omim.org/entry/612069)
[TAR DNA-BINDING PROTEIN; TARDBP](https://omim.org/entry/605078)
TARDBP-related amyotrophic lateral sclerosis (TARDBP-related ALS) is characterized by upper motor neuron (UMN) and lower motor neuron (LMN) disease that appears indistinguishable from ALS of other known and unknown causes based on gender ratio, age of onset, symptom distribution, and severity of disease. The male to female ratio is 1.6 to 1. Mean age of onset is 54 ± 12 years. UMN manifestations can include stiffness, spasticity, hyperreflexia, and pseudobulbar (paralysis of the bulbar nerves) affect; LMN manifestations often include weakness accompanied by muscle atrophy, fasciculations, and cramping. Limb-onset occurs in 80% and bulbar (hindbrain)-onset in 20%. Affected individuals typically succumb to respiratory failure when phrenic and thoracic motor neurons become severely involved. [from GeneReviews, TARDBP-Related Amyotrophic Lateral Sclerosis, pubmed:20301761 2015.02.13]
This form of autosomal dominant amyotrophic lateral sclerosis, ALS10, is caused by heterozygous mutation in the TARDBP gene, which encodes the TDP-43 protein. [from OMIM:612069, 2015.02.11]. Mouse model: Overexpression of wild-type human TARDBP in mice results in a dose-dependent neurodegeneration phenotype similar to ALS (Wils, et al., 2010, pubmed:20133711). [from OMIM:605078, 2015.02.11]
Bunina bodies (small eosinophilic neuronal inclusions, typically between 2 and 5 microns, often arranged in beaded chains) and ubiquitin-positive skein-like inclusions were found in the remaining lower motor neurons, and ubiquitin-positive intracytoplasmic inclusions were also found in the putaminal small neurons. (Tagawa et al., 2007, pubmed:17036243) [from OMIM:612069, 2015.02.11]. Mouse model: Cells with TDP-43-positive, ubiquitin-positive neuronal cytoplasmic inclusions (NCIs) and TDP-43-deleted nuclei appeared in transgenic mouse brains in an age-dependent manner. Tsai et al., 2010 (pubmed:20660618) concluded that increased levels of TDP-43 protein in forebrain are sufficient to lead to formation of TDP43-positive, ubiquitin-positive NCIs and neurodegeneration. [from OMIM:605078, 2015.02.11]
The poly-A-binding protein PABPC1 is mislocalized in spinal cord motor neurons of ALS patients; it is present in robust cytoplasmic inclusions in 13+/-4% of neurons in primary culture examined, vs. a diffuse cytoplasmic distribution in control neurons.
The TARDBP gene encodes the 43-kD TAR DNA-binding protein (TDP-43), which was originally identified as a transcriptional repressor that binds to TAR DNA of human immunodeficiency virus type 1. It is also involved in regulation of gene expression and splicing. (summary by Benajiba et al., 2009, pubmed:19350673) [from OMIM:605078, 2015.02.11]
40 of 44 identified mutations of the TARDBP gene that have been associated with familial or sporadic amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD) have been mapped to a C-terminal glycine-rich prion-like domain of the TARDBP protein.
A recent emerging theme in ALS research is the hypothesis that some ALS-associated proteins have a key role in the formation and function of cytoplasmic RNP stress granules, a cytosolic component in which non-functional translation initiation products accumulate. Stress granules form in response to a number of environmental stresses known to impede translation of mRNA into protein. Several ALS-associated proteins that have prion-like domains have been identified as accumulating in stress granules, including TARDBP.
One to many: 1 human to 2 Drosophila (See DIOPT, link below).
Ortholog of human TARDBP (2 Drosophila to 1 human).
Dmel\TBPH shares 40% identity and 53% similarity with human TARDBP.