title: Functional and Morphological Correlates in the Drosophila LRRK2 loss-of-function Model of Parkinson's Disease: Drug Effects of Withania somnifera (Dunal) Administration.
abstract: The common fruit fly Drosophila melanogaster (Dm) is a simple animal species that contributed significantly to the development of neurobiology whose leucine-rich repeat kinase 2 mutants (LRRK2) loss-of-function in the WD40 domain represent a very interesting tool to look into physiopathology of Parkinson's disease (PD). Accordingly, LRRK2 Dm have also the potential to contribute to reveal innovative therapeutic approaches to its treatment. Withania somnifera Dunal, a plant that grows spontaneously also in Mediterranean regions, is known in folk medicine for its anti-inflammatory and protective properties against neurodegeneration. The aim of this study was to evaluate the neuroprotective effects of its standardized root methanolic extract (Wse) on the LRRK2 loss-of-function Dm model of PD. To this end mutant and wild type (WT) flies were administered Wse, through diet, at different concentrations as larvae and adults (L+/A+) or as adults (L-/A+) only. LRRK2 mutants have a significantly reduced lifespan and compromised motor function and mitochondrial morphology compared to WT flies 1% Wse-enriched diet, administered to Dm LRRK2 as L-/A+and improved a) locomotor activity b) muscle electrophysiological response to stimuli and also c) protected against mitochondria degeneration. In contrast, the administration of Wse to Dm LRRK2 as L+/A+, no matter at which concentration, worsened lifespan and determined the appearance of increased endosomal activity in the thoracic ganglia. These results, while confirming that the LRRK2 loss-of-function in the WD40 domain represents a valid model of PD, reveal that under appropriate concentrations Wse can be usefully employed to counteract some deficits associated with the disease. However, a careful assessment of the risks, likely related to the impaired endosomal activity, is required.
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Francescaelena
authors.initials: F
authors.lastname: De Rose
authors.affiliation: Nanochemistry Department, Fondazione Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Marotta
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Poddighe
authors.affiliation: Institute of Neuroscience, National Research Council (CNR), Monserrato, Cagliari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Talani
authors.affiliation: Nanochemistry Department, Fondazione Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Catelani
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Setzu
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Solla
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marrosu
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Sanna
authors.affiliation: Pinnacle Biomedical Research Institute, Bhopal, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kasture
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Acquas
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Liscia
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D029721:Drosophila Proteins / Q000172:deficiency* / Q000235:genetics; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000254:growth & development; D004353:Drug Evaluation, Preclinical; D011992:Endosomes / Q000187:drug effects; D017952:Ganglia, Invertebrate / Q000187:drug effects / Q000648:ultrastructure; D007814:Larva; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008124:Locomotion / Q000187:drug effects; D008136:Longevity / Q000187:drug effects; D000432:Methanol; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000187:drug effects / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D018517:Plant Roots / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects; D016037:Single-Blind Method; D055366:Synaptic Potentials / Q000187:drug effects; D032341:Withania / Q000737:chemistry*
chemical_list: D000978:Antiparkinson Agents; D029721:Drosophila Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D000432:Methanol; D010936:Plant Extracts; D017346:Protein Serine-Threonine Kinases; C543697:LRRK protein, Drosophila