中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (10): 2095-2096.doi: 0.4103/1673-5374.391332

• 观点:退行性病与再生 • 上一篇    下一篇

构象动力学作为朊病毒蛋白错误折叠和神经毒性的内在决定因素

  

  • 出版日期:2024-10-15 发布日期:2024-01-29

Conformational dynamics as an intrinsic determinant of prion protein misfolding and neurotoxicity

Alessandro Cembran#, Pedro Fernandez-Funez*, ##br#   

  1. Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN, USA (Cembran A)
    Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, Duluth, MN, USA (Fernandez-Funez P)
  • Online:2024-10-15 Published:2024-01-29
  • Contact: Pedro Fernandez-Funez, PhD, pfernand@d.umn.edu.
  • Supported by:
    This work was supported by the NIH grant 7R21NS096627-02 to PFF and the Winston and Maxine Wallin Neuroscience Discovery Fund award CON000000083928 to PFF and AC.

摘要: https://orcid.org/0000-0002-0103-5593 (Pedro Fernandez-Funez)

Abstract: The prion protein (PrP) is the key molecular and pathological mediator of prion diseases, a heterogeneous group of brain disorders with fatal outcomes. Prion diseases are rare but deserve special attention because of their unique familial, sporadic, and transmissible etiologies, all caused by a single agent: misfolded conformations of PrP. The novel transmission of prion diseases captured the imagination of generations of scientists set on uncovering the molecular mechanisms underlying protein misfolding: seeded polymerization. This novel mechanism now appears to underlie not only prion diseases but also a group of highly prevalent brain disorders that include Alzheimer’s and Parkinson’s diseases among others, making the study of PrP misfolding highly significant. PrP is a small, secreted protein attached to the extracellular aspect of the membrane. It contains an unstructured N-terminus and a small globular domain with three α-helices and a short β-sheet. Misfolded and aggregated PrP into macromolecular assemblies is assumed to underlie both neuropathology and transmissibility of prion diseases. Recent models propose that different PrP species, including soluble, insoluble, and protease-resistant assemblies, are responsible for different aspects of prion disease pathology. Regardless of the identity of the PrP species responsible for pathology, the key pathological event is the misfolding of this abundant protein. The overall structural differences between physiological PrPC (cellular) and pathogenic PrPres (protease resistant) are well documented, including an increase in β-sheet content (from 3% to > 40%) that promotes self-assembly (Pan et al., 1993; Perez et al., 2010; Christen et al., 2013). Despite the extensive resources generated to examine PrP structure, we still have a limited knowledge about the molecular mechanism regulating PrP conformational dynamics and the initiation of misfolding.