Abstract
Cytoplasmic aggregation of Tar-DNA/RNA binding protein 43 (TDP-43) occurs in 97 percent of amyotrophic lateral sclerosis (ALS), ~40% of frontotemporal dementia (FTD) and in many cases of Alzheimer’s disease (AD). Cytoplasmic TDP-43 inclusions are seen in both sporadic and familial forms of these disorders, including those cases that are caused by repeat expansion mutations in the C9orf72 gene. To identify downstream mediators of TDP-43 toxicity, we expressed human TDP-43 in a subset of Drosophila motor neurons. Such expression causes age-dependent deficits in negative geotaxis behavior. Using this behavioral readout of locomotion, we conducted an shRNA suppressor screen and identified 32 transcripts whose knockdown was sufficient to ameliorate the neurological phenotype. The majority of these suppressors also substantially suppressed the negative effects on lifespan seen with glial TDP-43 expression. In addition to identification of a number of genes whose roles in neurodegeneration were not previously known, our screen also yielded genes involved in chromatin regulation and nuclear/import export- pathways that were previously identified in the context of cell based or neurodevelopmental suppressor screens. A notable example is SF2, a conserved orthologue of mammalian SRSF1, an RNA binding protein with roles in splicing and nuclear export. Our identification SF2/SRSF1 as a potent suppressor of both neuronal and glial TDP-43 toxicity also provides a convergence with C9orf72 expansion repeat mediated neurodegeneration, where this gene also acts as a downstream mediator.
Highlights
Protein aggregation pathology of Tar-DNA/RNA binding protein 43 (TDP-43) is a central feature in a suite of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer’s disease (AD) or those with an AD like presentation (Limbic-predominant Age-related TDP-43 Encephalopathy, LATE) [1]
Protein aggregation pathology of TDP-43 is a central feature in a suite of neurodegenerative disorders, including ALS, FTD and AD or those with an AD like presentation (Limbic-predominant Age-related TDP-43 Encephalopathy, LATE) [1]
Familial forms of ALS that exhibit TDP-43 proteinopathy include the rare cases that are caused by mutations in the TDP-43 protein coding region [11,12], and those caused by C9orf72 repeat expansions [13], which is the most common genetic cause of ALS and FTD in the USA
Summary
Protein aggregation pathology of TDP-43 is a central feature in a suite of neurodegenerative disorders, including ALS, FTD and AD or those with an AD like presentation (Limbic-predominant Age-related TDP-43 Encephalopathy, LATE) [1]. In ALS in particular, TDP-43 protein pathology is seen in ~97% of patient’s post mortem tissue from affected brain regions [2]. The pathological mislocalization into cytoplasmic inclusions will involve a loss of nuclear function and may produce toxic cytoplasmic effects as well. Such pathology is seen across the majority of both familial (fALS) and sporadic (sALS) cases. Familial forms of ALS that exhibit TDP-43 proteinopathy include the rare cases that are caused by mutations in the TDP-43 protein coding region [11,12], and those caused by C9orf repeat expansions [13], which is the most common genetic cause of ALS and FTD in the USA
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