title: Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease.
abstract: Common neurodegenerative proteinopathies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aß or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aß induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest that Drosophila may be useful for revealing determinants of neuronal dysfunction that precede cell loss, including synaptic changes, in the adult nervous system.
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Chouhan
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Caiwei
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Mumine
authors.initials: M
authors.lastname: Senturk
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Yarong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
authors.forename: Shreyasi
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA.|Department of Neurology, University of Texas Medical Branch, Galveston, TX, 77555, USA.|Parkinson's Disease Research, Education, and Clinical Center, Michael E. DeBakey VA Medical Center, Houston, TX, 77030, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Jackson
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund Street, Suite N.1150, Houston, TX, 77030, USA.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu.|Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu.|Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund Street, Suite N.1150, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D016923:Cell Death / Q000502:physiology*; D004195:Disease Models, Animal; D004330:Drosophila; D004596:Electroretinography; D005260:Female; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D008839:Microelectrodes; D046529:Microscopy, Electron, Transmission; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D014785:Vision, Ocular / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D010446:Peptide Fragments; C497604:SNCA protein, human; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer disease; Amyloid-beta peptide; Animal model; Drosophila; MAPT; Neurodegeneration; Neurophysiology; Parkinson disease; SNCA; Synapses; Tau; alpha-synuclein