2021
DOI: 10.1186/s40478-021-01148-z
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TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

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… Show more

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Cited by 14 publications
(27 citation statements)
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References 121 publications
(147 reference statements)
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“…Restoring Dlp by overexpression, in motor neurons specifically, restores Dlp expression at the synaptic terminal and mitigates TDP-43-dependent locomotor deficits. Importantly, these findings align with ALS patient data indicating that GPC6 protein, a human homolog of Dlp, accumulates in puncta within the spinal cord, mimicking the Dlp accumulations in the Drosophila ventral cord neuropil ( Lehmkuhl et al, 2021 ). Additional targets identified in Drosophila using TRAP include metabolic pathways (e.g., pentose phosphate, nuclear encoded components electron transport chain components, oxidative stress).…”
Section: Translation Dysregulation In Tdp-43 Proteinopathysupporting
confidence: 81%
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“…Restoring Dlp by overexpression, in motor neurons specifically, restores Dlp expression at the synaptic terminal and mitigates TDP-43-dependent locomotor deficits. Importantly, these findings align with ALS patient data indicating that GPC6 protein, a human homolog of Dlp, accumulates in puncta within the spinal cord, mimicking the Dlp accumulations in the Drosophila ventral cord neuropil ( Lehmkuhl et al, 2021 ). Additional targets identified in Drosophila using TRAP include metabolic pathways (e.g., pentose phosphate, nuclear encoded components electron transport chain components, oxidative stress).…”
Section: Translation Dysregulation In Tdp-43 Proteinopathysupporting
confidence: 81%
“…Several reports highlight TDP-43 dependent alterations in translation that may be indirect, resulting from impaired cellular homeostasis. When used in mouse or Drosophila models of TDP-43 proteinopathy, Translating Ribosomes Affinity Purification (TRAP) revealed complex changes in several targets and pathways within the in vivo motor neuron translatome, including RNA metabolism and cytoplasmic translation itself ( MacNair et al, 2016 ; Lehmkuhl et al, 2021 ). Additionally, TDP-43 overexpression in Drosophila has been shown to cause the phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha), an indicator of stress granule formation and consequently, translational repression ( Kim et al, 2014 ).…”
Section: Translation Dysregulation In Tdp-43 Proteinopathymentioning
confidence: 99%
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