title: Chronological requirements of TDP-43 function in synaptic organization and locomotive control.
abstract: Alterations in TDP-43 are commonly found in patients suffering from amyotrophic lateral sclerosis (ALS) and the genetic suppression of the conserved homologue in Drosophila (TBPH) provokes alterations in the functional organization of motoneuron synaptic terminals, resulting in locomotive defects and reduced life span. To gain more insight into this pathological process, it is of fundamental importance to establish when during the fly life cycle the lack of TBPH affects motoneuron activity and whether this is a reversible phenomenon. To achieve this, we conditionally expressed the endogenous protein in TBPH minus Drosophila neurons and found that TBPH is a short lived protein permanently required for Drosophila motility and synaptic assembly through the direct modulation of vesicular proteins, such as Syntaxin 1A, indicating that synaptic transmission defects are early pathological consequences of TBPH dysfunction in vivo. Importantly, TBPH late induction is able to recover synaptogenesis and locomotion in adult flies revealing an unexpected late-stage functional and structural neuronal plasticity. These observations suggest that late therapeutic approaches based on TDP-43 functionality may also be successful for the human pathology.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Romano
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Klima
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Buratti
authors.affiliation: VIB Center for the Biology of Disease, Leuven, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy. Electronic address: francisco.baralle@icgeb.org.
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Baralle
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy. Electronic address: fabian.feiguin@icgeb.org.
authors.forename: Fabian
authors.initials: F
authors.lastname: Feiguin
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006727:Hormone Antagonists / Q000008:administration & dosage; D006735:Horseradish Peroxidase / Q000378:metabolism; D007814:Larva; D008124:Locomotion / Q000235:genetics*; D015735:Mifepristone / Q000008:administration & dosage; D009046:Motor Neurons / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009420:Nervous System / Q000166:cytology*; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013569:Synapses / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051273:Glucose Transporter Type 2; D006727:Hormone Antagonists; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C000589036:TBPH protein, Drosophila; D049452:Green Fluorescent Proteins; D015735:Mifepristone; D006735:Horseradish Peroxidase
keywords: ALS; Drosophila; Neuromuscular junction; Syntaxin1A; TDP-43