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Planning for Prevention of Parkinson’s: A trial design forum

2024; IOS Press; Volume: 14; Issue: 3 Linguagem: Inglês

10.3233/jpd-249002

1877-718X

Grace F. Crotty, Michael A. Schwarzschild, Daniela Berg, Tanya Simuni, Caroline M. Tanner, Jessi L. Keavney, Katherine F. Callahan, Simona Eleuteri, Tracy-Shi Zhangfang, Michele Persico, Gianni Cutillo, David K. Simon, William Barbosa, Meghan Pawlik, E.J.K.B. Banda, Renée Wilson, Peggy Auinger, Ray Dorsey, Saloni Sharma, Robert G. Holloway, Roy N. Alcalay, Ruth B. Schneider,

Autism Spectrum Disorder Research

Background:We assessed the effects of a pharmacological approach to stabilize the retromer complex in a Parkinson's disease (PD) mouse model.Missense mutations in the VPS35 gene are a rare cause of familial PD.The VPS35 protein is a subunit of the retromer cargo recognition complex and regulates multiple pathways within neurons, some of which are potentially relevant for the pathophysiology of PD.Prior studies have revealed a role for the retromer complex in controlling accumulation and clearance of -synuclein aggregates.We previously identifi ed an aminoguanidine hydrazone, 1,3 phenyl bis guanylhydrazone (compound 2a), as a pharmacological stabilizer of the retromer complex that increases retromer subunit protein levels and function.Recent data emphasized that VPS35 is also a key regulator of Synuclein degradation pathways.Methods: Here, we assessed the effi cacy of 2a in protecting against Synuclein pathology and dopaminergic neuronal degeneration in a PD mouse model generated by unilateral injection of AAV-A53T-Synuclein in the substantia nigra.Moreover, we analyzed the effect of 2a on Syn degradation pathways in neuroblastoma cell lines.Results: Daily intraperitoneal administration of 2a at 10 mg/Kg for 100 days, led to robust protection against behavioral defi cits, dopaminergic neuronal loss and loss of striatal dopaminergic fi bers and striatal monoamines in PD mouse model.Treatment with 2a activated Synuclein degradation pathways in the SN and led to signifi cant reductions in aggregates and pathological Synuclein.We analyzed the effect of 2a administration on the main Syn degradation pathways in SH-SY5Y neuroblastoma cells, and we found a signifi cant impact of 2a on macroautophagy, CMA and the proteasomal system. Conclusion:These data suggest retromer stabilization as a promising therapeutic intervention for PD leading to neuroprotection of dopaminergic neurons and attenuation of the accumulation of Synuclein pathology.These data highlight 2a or other regulators of the retromer complex as potential clinical drug candidates for future testing in PD patients.the app as assessed with a translated version of the System Usability Scale (SUS, range 0-100) and measures of physical fi tness and motor-and non-motor functioning. Results:Step counts per day increased over 4 weeks in a dose-dependent pattern (mean±SD: min-imal=1064±1030, moderate=1689±2060, large= 2745±3817).Usability of the STEPWISE app was perceived as excellent (SUS 86.6±12.7).Movement Disorders Society-Unifi ed Parkinson's Disease Rating Scale total scores declined signifi cantly in all groups, without group differences. Conclusion:This study provides preliminary evidence for target engagement of a remote, smartphonebased exercise intervention in people with PD.This motivates and supports further development of a smartphone application to increase physical activity in people with manifest PD.This approach could potentially motivate people with PD all over the world to become -and stay -physically active.We need trials studying the effectiveness of such an application for secondary prevention of PD, primary prevention of PD, and treatment and prevention of other neurodegenerative diseases.