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

Abstract

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/Vps13A disease (ChAc) is a devastating, life-shortening disorder characterized by acanthocytosis, neurodegeneration and abnormal proteostasis. We recently developed a Vps13a−/− ChAc-mouse model, showing acanthocytosis, neurodegeneration and neuroinflammation which could be restored by LYN inactivation. Here, we show in our Vps13a−/− 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 Vps13a−/− PRX5 expression was increased independent of age. LYN deficiency or nilotinib-mediated LYN inhibition improved autophagy in Vps13a−/− mice. In Vps13a−/−; Lyn−/− basal ganglia, absence of LYN resulted in reduced NRF2 activation and down-regulated expression of PRX2/5, SRXN1 and TRXR. Nilotinib treatment of Vps13a−/− 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.

Yeast as a Model to Find New Drugs and Drug Targets for VPS13-Dependent Neurodegenerative Diseases

“…Although a partial restoration of the actin cytoskeleton was observed in red blood cells, the lack of improvement of neurological symptoms was noted after six-month drug administration [123]. Further, studies on mice models revealed that the drug tested, dasatinib, is not able to cross the blood-brain barrier, but another potential kinase inhibitor, nilotinib, can do that and improve not only haematological but also neurological defects in mice [124,125]. Since the variety of potential treatments is very limited, there is a great need for new drug candidates which could be effective in ChAc patients.…”

“…Newly identified potential repurposable drugs which are effective in alleviating defects of yeast mutant cells, such as calcineurin inhibitors, flavonoids and copper ionophores, require intensive studies using available human cell and mouse models. HeLa siVPS13A [83], fibroblasts or red blood cells from patients and patient-derived neuronal cell models [211] together with a mouse model of ChAc [124] will help to answer the question of whether any of these drugs can be of use for intervention in ChAc and other VPS13-related diseases.…”