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bioRxiv · 10.1101/2025.01.17.633690

Differential regulation of brain-specific molecular pathways is the reason for curcumin adult life-phase specific DAergic neuroprotection: Insights from ALSS Drosophila model of Parkinson disease

Das, A.·Yenisetti, S. C.
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Abstract

AbstractCurcumin (CU), a bioactive compound of turmeric, has been put forward as a "golden molecule" due to its anti-inflammatory, antioxidant, hepatoprotective, neuroprotective, and anti-cancer ability, as proven by research conducted over the decade and more. Our laboratory, developed an adult life stage specific (ALSS) Drosophila model of sporadic Parkinsons disease (PD), and for first time demonstrated that dopaminergic (DAergic) neuroprotective efficacy of curcumin is limited to health phase viz. adult-young life stage and is absent during transition phase viz. adult senior life stages when PD set in. This observation suggests the limitation of curcumin as a therapeutic agent for late-onset disorders like PD. Further, our laboratory also demonstrated that despite curcumins ability to sequester oxidative stress during both the adult life stages, neuroprotection and brain dopamine replenishment is granted only in health stages but not in a vulnerable transition stage, which prompted to put forward the hypothesis that the molecular target(s) of CU, may be absent or inadequate in the transition stage of aging brain. With this insight, the current study was implemented to analyse the life stage-specific differential regulation of multiple molecular players of neuro-integral pathways in brain of ALSS Drosophila model of PD with curcumin intervention. It is discovered that curcumin-mediated health phase-specific neuroprotection underlies the correction of an altered expression of 1. dFOXO, GADD45, Puc of Bsk-dFOXO stress response pathway, 2. Mfn2 of Mitochondrial dynamics 3. CncC, GCLC, Prx 2540 -1,2, Jafrac1, Prx3 of Phase II antioxidant defense system pathway. Further, it is discovered that significant aging-associated naturally altered expression of certain molecular targets exists, that may contribute to the limitation of curcumins DAergic neuroprotective efficacy during the adult-transition stage. This knowledge will help in developing altered therapeutic strategies for PD as molecular targets of curcumin are conserved among fly, mice and human.

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Das, A., Yenisetti, S. C.. 2025-01-18. Differential regulation of brain-specific molecular pathways is the reason for curcumin adult life-phase specific DAergic neuroprotection: Insights from ALSS Drosophila model of Parkinson disease. https://doi.org/10.1101/2025.01.17.633690

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