Antibody conjugated targeted nanotherapy epigenetically inhibits calpain-mediated mitochondrial dysfunction to attenuate Parkinson's disease.

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  • Additional Information
    • Source:
      Publisher: Elsevier Applied Science Publishers Country of Publication: England NLM ID: 8307156 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-1344 (Electronic) Linking ISSN: 01448617 NLM ISO Abbreviation: Carbohydr Polym Subsets: MEDLINE
    • Publication Information:
      Publication: <1992-> : Barking : Elsevier Applied Science Publishers
      Original Publication: London [Eng.] : Applied Science Publishers, c1981-
    • Subject Terms:
      Mitochondria*/drug effects ; Mitochondria*/metabolism ; Calpain*/metabolism ; Calpain*/genetics ; Parkinson Disease*/drug therapy ; Nanoparticles*/chemistry ; Chitosan*/chemistry; Animals ; Humans ; Mice ; Epigenesis, Genetic/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Polycomb Repressive Complex 1/genetics ; Polycomb Repressive Complex 1/metabolism ; Cell Survival/drug effects ; Male ; Mice, Inbred C57BL
    • Abstract:
      Many neurodegenerative and psychiatric malignancies like Parkinson' disease (PD) originate from an imbalance of 17β-Estradiol (E2) in the human brain. However, the peripheral side effects of the usage of E2 for PD therapy and less understanding of the molecular mechanism hinder establishing its neurotherapeutic potential. In the present work, systemic side effects were overcome by targeted delivery using Dopamine receptor D3 (DRD3) conjugated E2-loaded chitosan nanoparticles (Ab-ECSnps) that showed a promising delivery to the brain. E2 is a specific calpain inhibitor that fosters neurodegeneration by disrupting mitochondrial function, while B-cell-specific Moloney murine leukemia virus integration region 1 (BMI1), an epigenetic regulator, is crucial in preserving mitochondrial homeostasis. We showed the administration of Ab-ECSnps inhibits calpain's translocation into mitochondria while promoting the translocation of BMI1 to mitochondria, thereby conferring neurotherapeutic benefits by enhancing cell viability, increasing mitochondrial DNA copy number, and preserving mitochondrial membrane potential. Further, we showed a novel molecular mechanism of BMI1 regulation by calpain that might contribute to maintaining mitochondrial homeostasis for attenuating PD. Concomitantly, Ab-ECSnps showed neurotherapeutic potential in the in vivo PD model. We showed for the first time that our brain-specific targeted delivery might regulate calpain-mediated BMI1 expression, thereby preserving mitochondrial homeostasis to alleviate PD.
      Competing Interests: Declaration of competing interest There are no conflicts to declare.
      (Copyright © 2024 Elsevier Ltd. All rights reserved.)
    • Contributed Indexing:
      Keywords: 17β-Estradiol; Antibody conjugate; Calpain; Chitosan nanoparticles; Mitochondrial homeostasis; Parkinson's disease (PD)
    • Accession Number:
      EC 3.4.22.- (Calpain)
      9012-76-4 (Chitosan)
      EC 2.3.2.27 (Polycomb Repressive Complex 1)
    • Publication Date:
      Date Created: 20240908 Date Completed: 20240908 Latest Revision: 20240909
    • Publication Date:
      20240910
    • Accession Number:
      10.1016/j.carbpol.2024.122575
    • Accession Number:
      39245478