Genetic mouse models for Parkinson's disease display severe pathology in glial cell mitochondria

Abstract

We recently described mitochondrial pathology in neurons of transgenic mice with genes associated with Parkinson's disease (PD). Now we describe severe mitochondrial damage in glial cells of the mesencephalon in mice carrying a targeted deletion of parkin (PaKO) or overexpressing doubly mutated human alpha-synuclein (asyn). The number of mitochondria with altered morphology in glial cells is cell type-dependent, but always higher than in neurons. Interestingly, mitochondrial damage also occurs in mesencephalic glia of mice carrying mutated asyn controlled by the tyrosine hydroxylase promoter. Such mice do not show glial expression of the transgene, but show expression in neighboring neurons. However, we found strong overexpression of endogenous asyn in mesencephalic astrocytes from these mice. Cortical astrocytes neither display enhanced asyn expression nor mitochondrial damage. Cultivated mesencephalic astrocytes from newborn transgenic mice display various functional defects along with the morphological damage of mitochondria. First, the mitochondrial Ca(2+)-storage capacity is reduced in asyn transgenic mesencephalic astrocytes, but not in astrocytes from PaKO. Second, the expression of the mitochondrial protein PTEN-induced putative kinase is constitutively increased in asyn transgenic mice, while in PaKO it reacts to oxidative stress by overexpressing this protein along with other mitochondria-related proteins. Third, the neurotrophic effects exerted by control astrocytes, stimulating cortical neurons from healthy mice to develop longer processes and larger neuronal areas, are lacking in co-cultures with transgenic mesencephalic astrocytes. In summary, glial mitochondria from transgenic mice display morphological and functional alterations. Such transgenic astrocytes fail to influence neuronal differentiation, reflecting an important role that glia may play in PD pathogenesis.

α-Synuclein amino terminus regulates mitochondrial membrane permeability

“…A direct action of α-Syn on mitochondria was implied by the observed decrease in Δψ m , which has also been reported by others (Banerjee et al, 2010a;Feng et al, 2010). In α-Syn transgenic mice, morphological and functional alterations in the mitochondria of glia have been observed (Schmidt et al, 2011), while conformational changes in α-Syn from a closed to open configuration are induced through interactions with mitochondria (Banerjee et al, 2010b;Nakamura et al, 2008). Moreover, the N-terminal 32 amino acids of α-Syn contain a cryptic mitochondrial targeting signal (Devi et al, 2008).…”

Drosophila as a Model to Study Mitochondrial Dysfunction in Parkinson's Disease

“…Second, expression of human PINK1 (Clark et al 2006;Yang et al 2006) or PARKIN in Drosophila suppresses phenotypes caused by loss of function of PINK1 or parkin, respectively, suggesting that the human and fly proteins are functionally conserved. Third, cells from patients and/or mouse knockout models of PINK1 or parkin also show defects in mitochondrial morphology and/or mitochondrial respiration, particularly in complex I activity in a variety of cell types (Greene et al 2003;Muftuoglu et al 2004;Palacino et al 2004;Exner et al 2007;Hoepken et al 2007;Stichel et al 2007;Gautier et al 2008;Poole et al 2008;Wood-Kaczmar et al 2008;Dagda et al 2009;Gegg et al 2009;Morais et al 2009;Sandebring et al 2009;Grünewald et al 2010;Billia et al 2011;Schmidt et al 2011;Shim et al 2011). Fourth, in neurons derived from pluripotent stem cells from PD patients harboring PINK1 mutations, recruitment of Parkin to mitochondria is impaired (Seibler et al 2011).…”

Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

“…Indeed a recent communication has identified glial cell-specific mitochondrial damage in a genetic mouse model of PD overexpressing doubly mutated human -synuclein (Schmidt et al, 2011), and suggest this as a potential mechanism underlying PD pathogenesis. These data suggest that the pathological modification of α-synuclein (overexpression or nitration as observed in PD) is sufficient to trigger neuroinflammation and consequently initiate the neurodegenerative process.…”