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.

Differential effects of phytotherapic preparations in the hSOD1 Drosophila melanogaster model of ALS

“…that could be regarded as a destabilizing solution condition resulting as a consequence in loss of mitochondrial functionality and also in altered vescicle trafficking. Thus, in particular, Mpe treatment might enhance bruchpilot synthesis similarly to what we found in another neurodegenerative disease in PD-PINK1 B9 Drosophila mutants18, while Wse treatment might act by enhancing the vesicle trafficking as previously suggested in LRRK219. Moreover, in the context of current knowledge about the mechanism of action of these drugs, even if they do not specifically regard ALS, a few references provide insight on the mechanism by which these compounds exert their anti-inflammatory effects2829.…”

“…Accordingly to previous results, obtained with fly models of Parkinson’s disease1819, the hSOD1 mutants were treated with Wse or Mpe at 0.1% w/w in their standard diet starting from larvae stage (L + /A + ) or as adults only (L − /A + ). As shown by Kaplan-Meier survival curves, administration of Wse as L − /A + exerts great significant effects in mutant flies (Fig.…”

“…Accordingly, a number of neurodegenerative diseases, including Alzheimer’s111213 and Parkinson’s diseases141516171819 as well as ALS, object of this study2021, are heuristically modeled in Drosophila . However, despite the significant progress in the knowledge of the biological bases of the degenerative diseases, the hope to find an efficient treatment has been, so far, elusive, as no treatment can halt their progression, with the partial exception of the antiglutamatergic Riluzole ® .…”

“…In this context, given the results obtained in two different Drosophila models of Parkinson disease (PD-LRRK2-LOF and PD-PINK1 B9 -LOF) with the application of two methanolic extracts of parts of the medicinal plants, Withania somnifera and Mucuna pruriens widely used in the Ayurvedic medicine171819222324 for their potential effects on treating many central nervous system disorders, we deemed to investigate their effects on ALS symptoms. In order to obtain experimental data, we proceed to set up a neurophysiological, biochemical and histological investigation using the hSOD1-GOF Drosophila model of ALS.…”

Commentary: Identification of potential therapeutic compounds for Parkinson's disease using Drosophila and human cell models

“…This assay is a useful and easy method to evaluate locomotor ability in Drosophila, and is based on the negative geotactic behavior shown by this organism. It has been widely used to test the effectiveness of compounds to suppress motor deficits in Drosophila models of several neurodegenerative diseases, including familial PD based on mutations in SNCA [17][18][19][20][21] , LRRK2 [22][23][24] , PINK1 25,26 or parkin [27][28][29][30] . In our study, we selected 23 compounds already tested in humans and whose function or activity could be beneficial in a context of DJ-1β deficiency.…”