Objective: To provide new insights on the relationships occurring between mitochondria physiology and α-synuclein (α-syn) accumulation in an animal model of progressive neurodegeneration.

Background: In Parkinson’s disease the α-synuclein (α-syn) accumulation in the dopaminergic neurons can overburden the clearance mechanisms, increase production of reactive oxygen species affecting mitochondrial dynamics, thus eliciting the necrosis/apoptosis pathways that finally culminate in cellular death. A recent work shows that the inhibition of Drp1, a key protein involved in mitochondrion fission, is able to attenuate neurotoxicity and dopamine release deficits in mild models of Parkinson’s disease i.e. MPTP and PINK1 KO mice model.

Methods: Rats overexpressing the mutated form of α-synuclein (A53T) specifically in the substantia nigra pars compacta (SNc) are treated chronically with the Drp1 inhibitor mdivi-1 (20 mg/kg, i.p.). After eight weeks of daily injection of mdivi-1 (twice a day) or vehicle, we sacrificed the animals and processed the brain for the immunohistochemistry assays. We also measured the oxygen consumption rate and (OCR) and mitochondrial membrane potential (Δψm) in cells overexpressing α-syn and treated with mdivi-1.

Results: Rats that received mdivi-1 displayed a significant reduction of the phenotype and neurotoxicity induced by A53T compared with the vehicle treated animals. The reduced neurotoxicity is linked with the improvement of mitochondrion function as suggested by ability of mdivi-1 to restore the spare respiratory capacity.

Conclusions: With this study we provide new insights on the relationships occurring between mitochondria physiology and α-syn accumulation, showing a mitochondrion-related inhibition of α-syn aggregation (without interfering with the expression). Thereby we provide an already-exploitable pharmacological tool able to counteract the neurodegenerative process.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/drp1-inhibition-ameliorates-synuclein-mediated-neurodegeneration-in-rats/