Targeting FBXO48 with BC1618 promotes axon regeneration and alleviates symptoms of Parkinson’s disease
Rattachement africain : cn, hk. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Introduction Neurons depend on the ubiquitin system to maintain proteostasis, which plays crucial roles in processes of neuronal death and axon regeneration after injuries and diseases. Developing druggable targets within the ubiquitin system that simultaneously support neuroprotection and axon regeneration has been considered an attractive therapeutic strategy. Objectives To systematically identify druggable molecules within the ubiquitin signaling pathway and evaluate their efficacy in neuroprotection. Methods To this end, we screened 181 ubiquitination-related small-molecule compounds for neuroprotective effects by performing excitotoxic interventions in HT22 cell lines and mouse primary neurons. Subsequently, using a mouse optic nerve crush model, we demonstrated the neuroprotective effect of BC1618 through RGC survival and axon regeneration. To investigate the mechanism, we employed LC-MS, co-IP, and RNA-seq to delineate the BC1618-FBXO48-SERBP1 regulatory axis and its downstream regulation of mRNA expression. To further evaluate the translational potential of BC1618, we assessed cell survival rates and behavioral impairments using both MPTP-induced mouse Parkinson’s disease model and MPP + -induced apoptosis model of iPSC-derived dopaminergic neurons. Results We identified BC1618 as an effective neuroprotectant that prevented glutamate-induced excitotoxicity in vitro and enhanced neurite outgrowth in immature neurons. Additionally, we showed its effectiveness in an optic nerve crush model, where BC1618 supported RGC survival and encouraged axon regeneration. Mechanistically, BC1618 inhibited FBXO48-mediated K63-linked ubiquitination of SERBP1 at K52, which protected SERBP1 from autophagic degradation. Our findings established SERBP1 as a key regulator that coordinates downstream mRNA expression to mediate neuroprotection. Notably, our results demonstrated that BC1618 mitigated MPTP-induced degeneration of dopaminergic neurons and motor deficits, while also exhibiting robust neuroprotective effects in MPP + -stimulated human-derived dopaminergic neurons. Conclusions These findings highlight that targeting FBXO48 with BC1618 promotes axon regeneration and alleviates symptoms of Parkinson’s disease by reducing the degradation of SERBP1, revealing a novel therapeutic target for clinical translation.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Targeting FBXO48 with BC1618 promotes axon regeneration and alleviates symptoms of Parkinson’s disease
- Date Crossref
- 01/07/2026
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
Beijing Institute for Stem Cell and Regenerative Medicine pays non établi dans la noticeUniversité ou école supérieure
-
Sir Run Run Shaw Hospital pays non établi dans la noticeÉtablissement de santé
-
Union Hospital Beijing Institute for Stem Cell and Regenerative Medicine pays non établi dans la noticeÉtablissement de santé
-
Beijing Tongren Hospital pays non établi dans la noticeÉtablissement de santé
-
Capital Medical University Beijing Institute of Ophthalmology pays non établi dans la noticeUniversité ou école supérieure
-
Institute of Zoology pays non établi dans la noticeStructure de recherche
-
University of Chinese Academy of Sciences Key Laboratory of Organ Regeneration and Reconstruction pays non établi dans la noticeUniversité ou école supérieure
-
Zhejiang University School of Medicine Beijing Institute for Stem Cell and Regenerative Medicine pays non établi dans la noticeUniversité ou école supérieure
Beijing Institute for Stem Cell and Regenerative Medicine, Sir Run Run Shaw Hospital et Beijing Institute for Stem Cell and Regenerative Medicine — Union Hospital, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.