Expression in the mammalian retina of parkin and UCH-L1, two components of the ubiquitin-proteasome system

Departamento de Fisiología, Genética y Microbiología, Facultad de Ciencias, Universidad de Alicante, Alicante, Spain.
Brain research (Impact Factor: 2.84). 09/2010; 1352:70-82. DOI: 10.1016/j.brainres.2010.07.019
Source: PubMed


The ubiquitin-proteasome system (UPS) functions as a major degradation pathway for misfolded and damaged proteins with an important neuroprotective role in the CNS against a variety of cellular stresses. Parkin and ubiquitin C-terminal hydrolase L1 (UCH-L1) are two relevant components of the UPS associated with a number of neurodegenerative disorders. We here address the expression profile of parkin and UCH-L1 in the mammalian retina, with special emphasis on primates. We describe for the first time the presence of parkin in the retina of mammals, including humans. Parkin and UCH-L1 genes were expressed at the mRNA and protein levels in the retina of all species examined. The immunolocalization pattern of parkin was quite widespread, being expressed by most retinal neuronal types, including photoreceptors. UCH-L1 was localized to horizontal cells and specific subtypes of bipolar and amacrine cells, as well as to ganglion cells and their axons forming the nerve fiber layer. In rodents no UCH-L1 immunoreactivity was found in cone or rod photoreceptors, whereas this protein was present along the whole length of cones in all other mammals. Remarkably, UCH-L1 was expressed by dopaminergic amacrine cells of primates. The ample distribution of parkin and UCH-L1 in the mammalian retina, together with the crucial role played by the UPS in normal neuronal physiology in the brain, points to a participation of these two proteins in the ubiquitin-proteasomal pathway of protein degradation in most retinal cell types, where they could exert a protective function against neuronal stress.

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Available from: Julian Esteve-Rudd, Mar 10, 2014
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    • "Further evidences on the existence of multiple isoforms come from the conflicting data on their tissue and cellular distribution. Parkin protein is particularly abundant in the mammalian brain and retina [22, 23, 36, 48, 49]. In human, parkin immunoreactivity (IR) has been observed in SN, locus coeruleus, putamen, and frontal lobe cortex [22, 23]. "
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    ABSTRACT: Parkinson protein 2, E3 ubiquitin protein ligase ( PARK2 ) gene mutations are the most frequent causes of autosomal recessive early onset Parkinson’s disease and juvenile Parkinson disease. Parkin deficiency has also been linked to other human pathologies, for example, sporadic Parkinson disease, Alzheimer disease, autism, and cancer. PARK2 primary transcript undergoes an extensive alternative splicing, which enhances transcriptomic diversification. To date several PARK2 splice variants have been identified; however, the expression and distribution of parkin isoforms have not been deeply investigated yet. Here, the currently known PARK2 gene transcripts and relative predicted encoded proteins in human, rat, and mouse are reviewed. By analyzing the literature, we highlight the existing data showing the presence of multiple parkin isoforms in the brain. Their expression emerges from conflicting results regarding the electrophoretic mobility of the protein, but it is also assumed from discrepant observations on the cellular and tissue distribution of parkin. Although the characterization of each predicted isoforms is complex, since they often diverge only for few amino acids, analysis of their expression patterns in the brain might account for the different pathogenetic effects linked to PARK2 gene mutations.
    BioMed Research International 07/2014; 2014(3):690796. DOI:10.1155/2014/690796 · 3.17 Impact Factor
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    • "UEA-I (for EC), CD146 (for EC), CD133 (for PC), GGT (for brain) and S-100B (for brain) are used as detection markers. UCHL1 (also known as PGP9.5), which is a component of the ubiquitin proteosome system [47]–[48], was first detected as “brain-specific protein” in 1981 [48]. This protein has a more specific tissue distribution than S100B and is found more exclusively in neurons [34]. "
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    ABSTRACT: Despite aggressive research, central nervous system (CNS) disorders, including blood-brain barrier (BBB) injury caused by microbial infection, stroke, abused drugs [e.g., methamphetamine (METH) and nicotine], and other pathogenic insults, remain the world's leading cause of disabilities. In our previous work, we found that dysfunction of brain microvascular endothelial cells (BMECs), which are a major component of the BBB, could be caused by nicotine, meningitic pathogens and microbial factors, including HIV-1 virulence factors gp41 and gp120. One of the most challenging issues in this area is that there are no available cell-based biomarkers in peripheral blood for BBB disorders caused by microbial and non-microbial insults. To identify such cellular biomarkers for BBB injuries, our studies have shown that mice treated with nicotine, METH and gp120 resulted in increased blood levels of CD146+(endothelial marker)/S100B+ (brain marker) circulating BMECs (cBMECs) and CD133+[progenitor cell (PC) marker]/CD146+ endothelial PCs (EPCs), along with enhanced Evans blue and albumin extravasation into the brain. Nicotine and gp120 were able to significantly increase the serum levels of ubiquitin C-terminal hydrolase 1 (UCHL1) (a new BBB marker) as well as S100B in mice, which are correlated with the changes in cBMECs and EPCs. Nicotine- and meningitic E. coli K1-induced enhancement of cBMEC levels, leukocyte migration across the BBB and albumin extravasation into the brain were significantly reduced in alpha7 nAChR knockout mice, suggesting that this inflammatory regulator plays an important role in CNS inflammation and BBB disorders caused by microbial and non-microbial factors. These results demonstrated that cBMECs as well as EPCs may be used as potential cell-based biomarkers for indexing of BBB injury.
    PLoS ONE 04/2013; 8(4):e62164. DOI:10.1371/journal.pone.0062164 · 3.23 Impact Factor
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    • "Cryostat vertical sections and retinal whole-mounts were obtained and processed for immunolabeling following well established procedures (Cuenca and Kolb, 1998; Cuenca et al., 1995; Martínez-Navarrete et al., 2007; Esteve-Rudd et al., 2010). For objective comparison, retinas from control and rotenone-treated rats were fully processed in parallel, including their mounting and staining on the same slide (Cuenca et al., 2005). "
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    ABSTRACT: Rotenone is a widely used pesticide and a potent inhibitor of mitochondrial complex I (NADH-quinone reductase) that elicits the degeneration of dopaminergic neurons and thereby the appearance of a parkinsonian syndrome. Here we have addressed the alterations induced by rotenone at the functional, morphological and molecular levels in the retina, including those involving both dopaminergic and non-dopaminergic retinal neurons. Rotenone-treated rats showed abnormalities in equilibrium, postural instability and involuntary movements. In their outer retina we observed a loss of photoreceptors, and a reduced synaptic connectivity between those remaining and their postsynaptic neurons. A dramatic loss of mitochondria was observed in the inner segments, as well as in the axon terminals of photoreceptors. In the inner retina we observed a decrease in the expression of dopaminergic cell molecular markers, including loss of tyrosine hydroxylase immunoreactivity, associated with a reduction of the dopaminergic plexus and cell bodies. An increase in immunoreactivity of AII amacrine cells for parvalbumin, a Ca(2+)-scavenging protein, was also detected. These abnormalities were accompanied by a decrease in the amplitude of scotopic and photopic a- and b-waves and an increase in the b-wave implicit time, as well as by a lower amplitude and greater latency in oscillatory potentials. These results indicate that rotenone induces loss of vision by promoting photoreceptor cell death and impairment of the dopaminergic retinal system.
    Neurobiology of Disease 10/2011; 44(1):102-15. DOI:10.1016/j.nbd.2011.06.009 · 5.08 Impact Factor
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