Abstract
BackgroundMutation of PTEN-induced putative kinase 1 (PINK1) causes autosomal recessive early-onset Parkinson’s disease (PD). Despite of its ubiquitous expression in brain, its roles in non-neuronal cells such as neural stem cells (NSCs) and astrocytes were poorly unknown.ResultsWe show that PINK1 expression increases from embryonic day 12 to postnatal day 1 in mice, which represents the main period of brain development. PINK1 expression also increases during neural stem cell (NSC) differentiation. Interestingly, expression of GFAP (a marker of astrocytes) was lower in PINK1 knockout (KO) mouse brain lysates compared to wild-type (WT) lysates at postnatal days 1-8, whereas there was little difference in the expression of markers for other brain cell types (e.g., neurons and oligodendrocytes). Further experiments showed that PINK1-KO NSCs were defective in their differentiation to astrocytes, producing fewer GFAP-positive cells compared to WT NSCs. However, the KO and WT NSCs did not differ in their self-renewal capabilities or ability to differentiate to neurons and oligodendrocytes. Interestingly, during differentiation of KO NSCs there were no defects in mitochondrial function, and there were not changes in signaling molecules such as SMAD1/5/8, STAT3, and HES1 involved in differentiation of NSCs into astrocytes. In brain sections, GFAP-positive astrocytes were more sparsely distributed in the corpus callosum and substantia nigra of KO animals compared with WT.ConclusionOur study suggests that PINK1 deficiency causes defects in GFAP-positive astrogliogenesis during brain development and NSC differentiation, which may be a factor to increase risk for PD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0186-6) contains supplementary material, which is available to authorized users.
Highlights
Mutation of PTEN-induced putative kinase 1 (PINK1) causes autosomal recessive early-onset Parkinson’s disease (PD)
The expression levels of PINK1 increase during brain development, and glial fibrillary acidic protein (GFAP) expression is attenuated in PINK1-deficient mouse brains Since PINK1 is closely associated with the signaling pathways that regulate cell proliferation, survival, and differentiation [7,8,9], we first examined the expression levels of PINK1 during brain development during a period characterized by the vigorous proliferation and differentiation of brain cells
Neither GFAP mRNA expression nor signaling pathways involved in gliogenesis are changed in PINK1-deficient neural stem cells (NSCs) In an effort to identify the mechanisms responsible for decreasing the differentiation of PINK1-KO NSCs into GFAP-positive astrocytes, we examined the activation levels of the signaling molecules involved in astrogliogenesis, including STAT3 [36,37,38], SMAD1/5/8 [39], and HES1 [40]
Summary
Mutation of PTEN-induced putative kinase 1 (PINK1) causes autosomal recessive early-onset Parkinson’s disease (PD). PTEN-induced putative kinase 1 (PINK1) is a PDrelated gene whose mutation causes an autosomal recessive early-onset PD [1]. It regulates mitochondrial function [2], which is linked to ATP generation, oxygen consumption [3,4,5], and ROS production [6]. Astrocytes, which are the most abundant cells in the brain, express glial fibrillary acidic protein (GFAP) and are known to play important roles in developing, intact, and injured brains. Astrocytes regulate synaptogenesis [14], neural activity, and neural circuit formation in both developing and injured brains [15,16,17]. Astrocytes support neurons by providing nutrients and growth factors [18,19,20], and maintaining the homeostasis
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