Abstract
Calcium and integrin binding protein 1 (CIB1) is a calcium-binding protein that was initially identified as a binding partner of platelet integrin αIIb. Although CIB1 has been shown to interact with multiple proteins, its biological function in the brain remains unclear. Here, we show that CIB1 negatively regulates degeneration of dopaminergic neurons in a mouse model of Parkinson’s disease using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Genetic deficiency of the CIB1 gene enhances MPTP-induced neurotoxicity in dopaminergic neurons in CIB1−/− mice. Furthermore, RNAi-mediated depletion of CIB1 in primary dopaminergic neurons potentiated 1-methyl-4-phenyl pyrinidium (MPP+)-induced neuronal death. CIB1 physically associated with apoptosis signal-regulating kinase 1 (ASK1) and thereby inhibited the MPP+-induced stimulation of the ASK1-mediated signaling cascade. These findings suggest that CIB1 plays a protective role in MPTP/MPP+-induced neurotoxicity by blocking ASK1-mediated signaling.
Highlights
Parkinson’s disease is a neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and their targets in the striatum[1,2,3]
To better understand the in vivo function of Calcium and integrin binding protein 1 (CIB1) in the pathogenesis of Parkinson’s disease, we examined the effect of CIB1 gene deletion on loss of dopaminergic neurons in the SNpc in a MPTP mouse model of the disease
Immunohistochemical staining for tyrosine hydroxylase (TH) and stereological analysis revealed that MPTP treatment resulted in a more severe loss of TH-positive dopaminergic neurons in the SNpc of CIB1-knockout (CIB1−/−) mice, compared to that of wild-type mice (Fig. 1A,B)
Summary
Parkinson’s disease is a neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and their targets in the striatum[1,2,3]. Apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase (MAP3K) in the JNK pathway, is activated in a mouse model of Parkinson’s disease and mediates cell death of dopaminergic neurons[10,11]. CIB1 interacts with a number of proteins, including Rac[3] and several serine/threonine kinases such as polo-like kinases, focal adhesion kinase, and p21-activated kinase[18,19,20,21]. It physically associates with and inhibits ASK1, thereby preventing stress-induced apoptosis in a calcium ion-sensitive manner[22]. Our findings suggest that CIB1 mitigates MPTP/MPP+-induced neurotoxicity by targeting ASK1
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