MT-POM: neuroprotective effect in a Drosophila model of Parkinson’s disease

Authors:
Maria Antonietta Casu (1), Ignazia Mocci (1), Dong Seok Kim (2), Nigel H. Greig (3), Maria Dolores Setzu (4), Anna Rosa Carta (4)

Organisations:
1: CNR-Institute of Translational Pharmacology, Cagliari, Italy
2: Aevis Bio Inc., Daejeon, Republic of Korea
3: Intramural Research Program, National Institute On Aging, NIH, MD, USA
4: Department of Biomedical Sciences, University of Cagliari, Italy

Presenting author:
Maria Antonietta Casu

Exposition date:
Saturday, September 16, 2023

Exposition position:
125/2

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and motor impairment. The pathogenesis of PD may involve both genetic susceptibility and environmental factors. Mutations in Leucine-rich repeat kinase 2 (LRRK2) locus contributes to genetic forms of PD1. The common fruit fly Drosophila melanogaster (Dm) carrying the mutation LRRK2 loss-of-function in the WD40 domain (LRRK2-Dm), is an in vivo model of PD that develops motor impairment, dopaminergic neuronal loss and damaged mitochondria2. Therefore, this model can be considered a valid tool to first test novel therapeutic approaches to the disease.

Recent studies have identified several immunomodulatory agents with a neuroprotective effect in neurodegenerative disorders2-3. Here, in the LRRK2-Dm, we tested the novel pomalidomide derivative 3-monothiopomalidomide (MT-POM) that displayed increased potency in lowering TNF-alpha levels in in vitro tests. Changes in motor performance, number of brain dopaminergic neurons and mitochondria integrity were analyzed. Moreover, we studied the survival rate of LRRK2-Dm and wild type flies under life-long drug treatment.

Mutant and wild type flies received 3 increasing MT-POM doses via diet from day 1 post eclosion, and efficacy was evaluated after 21 days. MT-POM significantly and dose-dependently improved climbing behavior respect to controls, prevented the loss of dopaminergic neurons and fully rescued damaged mitochondria with dilated cristae observed in non-treated LRRK2-Dm. Moreover, MT-POM significantly extended the survival of LRRK2-Dm.

Our data indicate a neuroprotective effect of MT-POM in the LRRK2-Dm PD model, prompting further investigation of this drug in mammalian models of PD.

Refs:

1 West AB, et al., 2005

2 Casu et al., 2020

3 Martinez B, et al., 2019