Adaptative Up-Regulation of PRX2 and PRX5 Expression Characterizes Brain from a Mouse Model of Chorea-Acanthocytosis

• Main Authors: Enrica Federti (Author), Alessandro Matte (Author), Veronica Riccardi (Author), Kevin Peikert (Author), Seth L. Alper (Author), Adrian Danek (Author), Ruth H. Walker (Author), Angela Siciliano (Author), Iana Iatcenko (Author), Andreas Hermann (Author), Lucia De Franceschi (Author)
• Format: Book
• Published: MDPI AG, 2021-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

The peroxiredoxins (PRXs) constitute a ubiquitous antioxidant. Growing evidence in neurodegenerative disorders such as Parkinson's disease (PD) or Alzheimer's disease (AD) has highlighted a crucial role for PRXs against neuro-oxidation. Chorea-acanthocytosis/<i>Vps13A</i> disease (ChAc) is a devastating, life-shortening disorder characterized by acanthocytosis, neurodegeneration and abnormal proteostasis. We recently developed a <i>Vps13a^−/−</i> ChAc-mouse model, showing acanthocytosis, neurodegeneration and neuroinflammation which could be restored by LYN inactivation. Here, we show in our <i>Vps13a^−/−</i> mice protein oxidation, NRF2 activation and upregulation of downstream cytoprotective systems NQO1, SRXN1 and TRXR in basal ganglia. This was associated with upregulation of PRX2/5 expression compared to wild-type mice. PRX2 expression was age-dependent in both mouse strains, whereas only <i>Vps13a^−/−</i> PRX5 expression was increased independent of age. LYN deficiency or nilotinib-mediated LYN inhibition improved autophagy in <i>Vps13a^−/−</i> mice. In <i>Vps13a^−/−; Lyn^−/−</i> basal ganglia, absence of LYN resulted in reduced NRF2 activation and down-regulated expression of PRX2/5, SRXN1 and TRXR. Nilotinib treatment of <i>Vps13a^−/−</i> mice reduced basal ganglia oxidation, and plasma PRX5 levels, suggesting plasma PRX5 as a possible ChAc biomarker. Our data support initiation of therapeutic Lyn inhibition as promptly as possible after ChAc diagnosis to minimize development of irreversible neuronal damage during otherwise inevitable ChAc progression.

Item Description

10.3390/antiox11010076
2076-3921