Toxic aggregates of alpha-synuclein (alpha syn) are considered key drivers of Parkinson's disease (PD) pathology. In early PD, alpha syn induces synaptic dysfunction also modulating the glutamatergic neurotransmission. However, a more detailed understanding of the molecular mechanisms underlying alpha syn-triggered synaptic failure is required to design novel therapeutic interventions. Here, we described the role of Rabphilin-3A (Rph3A) as novel target to counteract alpha syn-induced synaptic loss in PD. Rph3A is a synaptic protein interacting with alpha syn and involved in stabilizing dendritic spines and in promoting the synaptic retention of NMDA-type glutamate receptors. We found that in vivo intrastriatal injection of alpha syn-preformed fibrils in mice induces the early loss of striatal synapses associated with decreased synaptic levels of Rph3A and impaired Rph3A/NMDA receptors interaction. Modulating Rph3A striatal expression or interfering with the Rph3A/alpha syn complex with a small molecule prevented dendritic spine loss and rescued associated early motor defects in alpha syn-injected mice. Notably, the same experimental approaches prevented alpha syn-induced synaptic loss in vitro in primary hippocampal neurons. Overall, these findings indicate that approaches aimed at restoring Rph3A synaptic functions can slow down the early synaptic detrimental effects of alpha syn aggregates in PD.

Rabphilin-3A as a novel target to reverse α-synuclein-induced synaptic loss in Parkinson's disease / E. Ferrari, D. Scheggia, E. Zianni, M. Italia, M. Brumana, L. Palazzolo, C. Parravicini, A. Pilotto, A. Padovani, E. Marcello, I. Eberini, P. Calabresi, M. Diluca, F. Gardoni. - In: PHARMACOLOGICAL RESEARCH. - ISSN 1096-1186. - 183:(2022 Sep), pp. 106375.1-106375.15. [10.1016/j.phrs.2022.106375]

Rabphilin-3A as a novel target to reverse α-synuclein-induced synaptic loss in Parkinson's disease

E. Ferrari
Primo
;
D. Scheggia
Secondo
;
E. Zianni;M. Italia;L. Palazzolo;C. Parravicini;E. Marcello;I. Eberini;M. Diluca
Penultimo
;
F. Gardoni
Ultimo
2022

Abstract

Toxic aggregates of alpha-synuclein (alpha syn) are considered key drivers of Parkinson's disease (PD) pathology. In early PD, alpha syn induces synaptic dysfunction also modulating the glutamatergic neurotransmission. However, a more detailed understanding of the molecular mechanisms underlying alpha syn-triggered synaptic failure is required to design novel therapeutic interventions. Here, we described the role of Rabphilin-3A (Rph3A) as novel target to counteract alpha syn-induced synaptic loss in PD. Rph3A is a synaptic protein interacting with alpha syn and involved in stabilizing dendritic spines and in promoting the synaptic retention of NMDA-type glutamate receptors. We found that in vivo intrastriatal injection of alpha syn-preformed fibrils in mice induces the early loss of striatal synapses associated with decreased synaptic levels of Rph3A and impaired Rph3A/NMDA receptors interaction. Modulating Rph3A striatal expression or interfering with the Rph3A/alpha syn complex with a small molecule prevented dendritic spine loss and rescued associated early motor defects in alpha syn-injected mice. Notably, the same experimental approaches prevented alpha syn-induced synaptic loss in vitro in primary hippocampal neurons. Overall, these findings indicate that approaches aimed at restoring Rph3A synaptic functions can slow down the early synaptic detrimental effects of alpha syn aggregates in PD.
Dendritic spines; Mice; Parkinson’s disease; Protein-protein interactions; Rabphilin-3A; α-synuclein;
Settore BIO/14 - Farmacologia
PRIN201719FGARD_01 - Role of alpha-synuclein and LRRK2 in Levodopa-induced dyskinesia - GARDONI, FABRIZIO - PRIN2017 - PRIN bando 2017 - 2019
PRIN201517FGARD - Targeting early synaptic dysfunctions induced by alpha-synuclein as a novel therapeutic approach in Parkinson's disease - GARDONI, FABRIZIO - PRIN2015 - PRIN bando 2015 - 2017
Article (author)
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S1043661822003206-main.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 6.06 MB
Formato Adobe PDF
6.06 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/937707
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact