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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.

plos one

Functional and Morphological Correlates in the Drosophila LRRK2 loss-of-function Model of Parkinson’s Disease: Drug Effects of Withania somnifera (Dunal) Administration