title: Aggregate formation prevents dTDP-43 neurotoxicity in the Drosophila melanogaster eye.
abstract: TDP-43 inclusions are an important histopathological feature in various neurodegenerative disorders, including Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degeneration. However, the relation of these inclusions with the pathogenesis of the disease is still unclear. In fact, the inclusions could be toxic themselves, induce loss of function by sequestering TDP-43 or a combination of both. Previously, we have developed a cellular model of aggregation using the TDP-43 Q/N rich amino acid sequence 331-369 repeated 12 times (12xQ/N) and have shown that these cellular inclusions are capable of sequestering the endogenous TDP-43 both in non-neuronal and neuronal cells. We have tested this model in vivo in the Drosophila melanogaster eye. The eye structure develops normally in the absence of dTDP-43, a fact previously seen in knock out fly strains. We show here that expression of EGFP 12xQ/N does not alter the structure of the eye. In contrast, TBPH overexpression is neurotoxic and causes necrosis and loss of function of the eye. More important, the neurotoxicity of TBPH can be abolished by its incorporation to the insoluble aggregates induced by EGFP 12xQ/N. This data indicates that aggregation is not toxic per se and instead has a protective role, modulating the functional TBPH available in the tissue. This is an important indication for the possible pathological mechanism in action on ALS patients.
authors.affiliation: ICGEB - International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Cragnaz
authors.affiliation: ICGEB - International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Raffaela
authors.initials: R
authors.lastname: Klima
authors.affiliation: ICGEB - International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Natasa
authors.initials: N
authors.lastname: Skoko
authors.affiliation: ICGEB - International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Budini
authors.affiliation: ICGEB - International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Fabian
authors.initials: F
authors.lastname: Feiguin
authors.affiliation: ICGEB - International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy. Electronic address: baralle@icgeb.org.
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Baralle
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity*; D004331:Drosophila melanogaster; D005123:Eye / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008027:Light; D018782:Maze Learning; D020258:Neurotoxicity Syndromes / Q000235:genetics* / Q000473:pathology*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C000589036:TBPH protein, Drosophila; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: ALS; Aggregate; Drosophila melanogaster; TBPH; TDP-43