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Abstract
The fruit fly Drosophila melanogaster (Dm) mutant for PTEN-induced putative kinase 1 (PINK1B9) gene is a powerful tool to investigate physiopathology of Parkinson's disease (PD). Using PINK1B9 mutant Dm we sought to explore the effects of Mucuna pruriens methanolic extract (Mpe), a L-Dopa-containing herbal remedy of PD. The effects of Mpe on PINK1B9 mutants, supplied with standard diet to larvae and adults, were assayed on 3–6 (I), 10–15 (II) and 20–25 (III) days old flies. Mpe 0.1% significantly extended lifespan of PINK1B9 and fully rescued olfactory response to 1-hexanol and improved climbing behavior of PINK1B9 of all ages; in contrast, L-Dopa (0.01%, percentage at which it is present in Mpe 0.1%) ameliorated climbing of only PINK1B9 flies of age step II. Transmission electron microscopy analysis of antennal lobes and thoracic ganglia of PINK1B9 revealed that Mpe restored to wild type (WT) levels both T-bars and damaged mitochondria. Western blot analysis of whole brain showed that Mpe, but not L-Dopa on its own, restored bruchpilot (BRP) and tyrosine hydroxylase (TH) expression to age-matched WT control levels. These results highlight multiple sites of action of Mpe, suggesting that its effects cannot only depend upon its L-Dopa content and support the clinical observation of Mpe as an effective medication with intrinsic ability of delaying the onset of chronic L-Dopa-induced long-term motor complications. Overall, this study strengthens the relevance of using PINK1B9 Dm as a translational model to study the properties of Mucuna pruriens for PD treatment.
Highlights
Parkinson’s disease (PD) is, after the Alzheimer’s disease, the second most prevalent neurodegenerative disease first affecting medulla oblongata, olfactory bulb and substantia nigra [1]
This study was aimed at characterizing the effects of the standardized extract of Mucuna pruriens seeds, known for possible neuroprotective effects in neurotoxin-induced models of PD [21] [22] and reduced risk of dyskinesias [14], in a genetic fly model of PD, the PINK1B9 mutant Drosophila melanogaster (Dm) [23]
The present results show that addition of 0.1% Mpe to the feeding medium of PINK1B9 mutants significantly a) improved climbing ability and olfaction, b) rescued compromised T-bars density and damaged mitochondria in the antennal lobes (ALs) and thoracic ganglia, c) restored to wild type (WT) control values the expression of BRP and tyrosine hydroxylase (TH) proteins
Summary
Parkinson’s disease (PD) is, after the Alzheimer’s disease, the second most prevalent neurodegenerative disease first affecting medulla oblongata, olfactory bulb and substantia nigra [1]. Loss of olfaction is a very consistent marker of PD occurring in 95% of patients early before the onset of motor symptoms [2]. Olfactory dysfunction is observed in PTEN-induced putative kinase 1 (PINK1B9) Parkinsonism, both in humans [3] and in animal models of PD [4]. The Drosophila melanogaster (Dm) PINK1B9 mutant model recapitulates several of the essential features of PD [5] and has been used to study neuronal dysfunction and molecular aspects of neurodegeneration [6]. PINK1B9 model provides major information regarding pathogenic molecular basis of early onset PD and mitochondrial dysfunction [5]. It was recently reported that PINK1 mutation enhances mitochondrial stress-induced neurodegeneration in mice [7]
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