Abstract
Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neuron function, culminating in death due to respiratory failure [32, 79]
These findings suggest that cytoplasmic TAR DNA binding protein 43 (TDP-43), which is a hallmark of disease, has multiple opportunities to cause alterations in the motor neuron proteome and contribute to pathogenesis
We hypothesized that while some of the translational alterations may be an indirect consequence of neurodegeneration, others are directly caused by TDP-43, possibly through mRNA association with, and sequestration into, TDP-43 cytoplasmic complexes
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neuron function, culminating in death due to respiratory failure [32, 79]. TDP-43 has been shown to influence the translation of specific mRNAs, both as a negative and a positive regulator [12, 14, 15, 67, 76]. Taken together these findings suggest a complex role for TDP-43 in translation regulation, which has been linked to the formation of TDP-43 cytoplasmic puncta in disease and altered protein expression and/or localization of its mRNA targets
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