title: Involvement of calpains in adult neurogenesis: implications for stroke.
abstract: Calpains are ubiquitous proteases involved in cell proliferation, adhesion and motility. In the brain, calpains have been associated with neuronal damage in both acute and neurodegenerative disorders, but their physiological function in the nervous system remains elusive. During brain ischemia, there is a large increase in the levels of intracellular calcium, leading to the activation of calpains. Inhibition of these proteases has been shown to reduce neuronal death in a variety of stroke models. On the other hand, after stroke, neural stem cells (NSC) increase their proliferation and newly formed neuroblasts migrate towards the site of injury. However, the process of forming new neurons after injury is not efficient and finding ways to improve it may help with recovery after lesion. Understanding the role of calpains in the process of neurogenesis may therefore open a new window for the treatment of stroke. We investigated the involvement of calpains in NSC proliferation and neuroblast migration in two highly neurogenic regions in the mouse brain, the dentate gyrus (DG) and the subventricular zone (SVZ). We used mice that lack calpastatin, the endogenous calpain inhibitor, and calpains were also modulated directly, using calpeptin, a pharmacological calpain inhibitor. Calpastatin deletion impaired both NSC proliferation and neuroblast migration. Calpain inhibition increased NSC proliferation, migration speed and migration distance in cells from the SVZ. Overall, our work suggests that calpains are important for neurogenesis and encourages further research on their neurogenic role. Prospective therapies targeting calpain activity may improve the formation of new neurons following stroke, in addition to affording neuroprotection.
authors.affiliation: Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve Faro, Portugal ; IBB-Institute for Biotechnology and Bioengineering, Center for Molecular and Structural Biomedicine, University of Algarve Faro, Portugal ; Center for Biomedical Research, CBMR, University of Algarve Faro, Portugal ; Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Machado
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Morte
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Carreira
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Azevedo
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute Wako-shi, Saitama, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Takano
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University Nagasaki, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute Wako-shi, Saitama, Japan.
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.affiliation: Department of Cell Biology, University of Virginia School of Medicine Charlottesville, VA, USA.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Asmussen
authors.affiliation: Department of Cell Biology, University of Virginia School of Medicine Charlottesville, VA, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Horwitz
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Caetana M
authors.initials: CM
authors.lastname: Carvalho
authors.affiliation: Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve Faro, Portugal ; IBB-Institute for Biotechnology and Bioengineering, Center for Molecular and Structural Biomedicine, University of Algarve Faro, Portugal ; Center for Biomedical Research, CBMR, University of Algarve Faro, Portugal ; Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Inês M
authors.initials: IM
authors.lastname: Araújo
keywords: calpains; calpastatin; hippocampus; migration; neurogenesis; proliferation; stroke; subventricular zone