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Selected Publication:

Type of publication: PhD Thesis
Type of document:

Year: 2012

Authors: Rupprecht, Anne

Title: Comparative Analysis of UCP2, UCP4 and UCP5.

Source: PhD-Arbeit, Vet. Med. Univ. Wien, pp. 123.


Authors Vetmeduni Vienna:

Rupprecht Anne

Advisor(s):
Pohl Elena

Reviewer(s):
Keller S
Rülicke Thomas

Vetmed Research Units:
Institute of Physiology, Pathohysiology and Biophysics, Unit of Physiology and Biophysics


Graduation date: 30.10.2012


Abstract:
Uncoupling proteins (UCPs) belong to the mitochondrial carrier superfamily and are proposed to transport protons, but accepted evidence exists only for UCP1. This protein mediates the non-shivering thermogenesis in brown adipose tissue. The functions of the other UCPs are controversial. Three UCPs - UCP2, UCP4 and UCP5 - were detected at mRNA level in neurons. They are proposed to regulate the mitochondrial generation of ROS and thereby to be involved in the pathogenesis of a wide range of diseases including neurodegenerative diseases. However, a simultaneous presence in the same cell of three proteins with the same function is very unlikely. To reveal the role of each protein - UCP2, UCP4 and UCP5 - we comparatively analysed their: (i) transport activity, (ii) expression pattern at mRNA and protein level and (iii) the putative involvement in ROS regulation. By quantitative mRNA analysis, we confirmed all three UCPs in brain with similar levels, but Western blot analysis revealed that only UCP4 is also significantly expressed at the protein level. We detected UCP4 mainly in neurons and to lesser extent in astrocytes. Moreover, we showed that UCP4 protein is present in neurosensory cells (outer and inner ear cells, Merkel cells of skin) indicating a strong association of UCP4 with all cells derived from neuronal progenitors. Functional investigations under oxidative stress conditions in the inner ear revealed no alteration of the UCP4 expression and do not support a ROS regulating function. Instead, UCP4 expression initiation coincides with the neurogenesis in embryonic brain and occurs simultaneously to the expression of neuronal marker during development of the inner ear indicating a neuro-specific UCP4 function. In contrast to UCP4, we determined a strong predominance of UCP2 at mRNA and protein level for cells and tissues associated with the immune system. We demonstrated that even in brain UCP2 expression is restricted to microglia cells – cells, which belong to the brain immune system. Analysing UCP2 levels in T-cells revealed a significant up-regulation of UCP2 after stimulation. Although we confirmed a UCP2 proton transport activity similar to UCP1, our results do not support a ROS regulation function of UCP2. The late up-regulation after T-cell stimulation and the further increase with re-stimulation indicate a role of UCP2 in later events of the immune response like proliferation, instead of the early signalling events involving ROS. Moreover, the UCP2 presence in stem cells and down-regulation with differentiation indicate an importance of UCP2 in highly proliferating cells. This makes an expression of UCP2 in neurons, which do not proliferate, even more unlikely. The expression in immune cells turns UCP2 into a potential tool in the pharmaceutical treatment of diseases with immunological background like neurodegenerative diseases. Moreover, UCP2 may also be useful in the modulation of unregulated cell proliferation in cancer.


Publication(s) resulting from University thesis:

Rupprecht, A; Bräuer, AU; Smorodchenko, A; Goyn, J; Hilse, KE; Shabalina, IG; Infante-Duarte, C; Pohl, EE (2012): Quantification of uncoupling protein 2 reveals its main expression in immune cells and selective up-regulation during T-cell proliferation. PLoS One. 2012; 7(8):e41406
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Smorodchenko, A; Rupprecht, A; Fuchs, J; Gross, J; Pohl, EE (2011): Role of mitochondrial uncoupling protein 4 in rat inner ear. Mol Cell Neurosci. 2011; 47(4):244-253

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