INTRANASAL DELIVERY OF HELICURE REDUCES Α-SYNUCLEIN OLIGOMERS, ALTERS AUTOPHAGY MECHANISMS, AND RESCUES MOTOR DEFICITS IN A PARKINSON’S DISEASE MOUSE MODEL

Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the accumulation of pathological α-synuclein (αSyn) aggregates. Physiologically, αSyn acts as a monomer, while its misfolding into oligomers is a key factor in neurodegeneration. Currently, therapies remain symptomatic, and there is no treatment to prevent PD. Here, we evaluated the efficacy of HeliCure, a selective peptide targeting αSyn oligomers, in a PD mouse model induced by AAV2/5-mediated overexpression of human wild-type αSyn in the SN. Control mice received an AAV2/5 empty vector, and six weeks after infusion, HeliCure was administered intranasally (0.87 μg/day) for 14 days. Motor function (open field, beam, cylinder, and rotarod tests) was assessed at 8 weeks post-AAV2/5 infusion. H-αSyn (monomeric, oligomeric and phosphorylated species), tyrosine hydroxylase (TH), the neuronal marker NeuN, glial markers (Iba1 and GFAP) and autophagy markers (LAMP1, LC3B and p62) were assessed in the striatum (CPu) and SN by WB and confocal microscopy. HeliCure-treated h-αSyn–overexpressing mice showed a significant reversal of motor deficits compared to controls. WB and confocal analyses revealed a reduction in monomeric, oligomeric and phosphorylated h-αSyn, accompanied by recovery of TH levels. NeuN expression remained unchanged, while Iba1 and GFAP levels were reduced in both regions of HeliCure-treated h-αSyn mice. Additionally, autophagy-related markers were modulated by HeliCure treatment. Our findings support the potential of HeliCure to suppress αSyn aggregation and restore functional deficits in a translational PD mouse model, with intranasal delivery highlighting its clinical potential as a disease-modifying therapy.