Novel in Situ Activity Assays for the Quantitative Molecular Analysis of Neurodegenerative Processes in the Retina

ISSN: 1875-533X (Online)
ISSN: 0929-8673 (Print)


Volume 21, 38 Issues, 2014


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Current Medicinal Chemistry

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Novel in Situ Activity Assays for the Quantitative Molecular Analysis of Neurodegenerative Processes in the Retina

Author(s): P.A.R. Ekström, M. Ueffing, E. Zrenner and F Paquet-Durand

Affiliation: Institute for Ophthalmic Research, University of Tübingen Röntgenweg 11, 72076 Tübingen, GERMANY

Abstract

The mechanisms of neuronal cell death are still only poorly understood, which has hindered the advancement of therapies for many currently untreatable neurodegenerative diseases. This calls for the development of new methods which reveal critical molecular mechanisms of the cell death machinery with both high sensitivity and cellular resolution. Using animal models for hereditary neurodegeneration in the retina, we have developed or adapted different biochemical assays to determine the enzymatic activities of calpain, poly-ADP-ribose-polymerase (PARP), and histone deacetylase (HDAC) directly and in situ. Additionally, the enzymatic activity of cGMP-dependent protein kinase (PKG) was assessed indirectly using in situ immunohistological techniques to detect PKG-activity-dependent products. Combining these assays with in situ cell death markers revealed close temporospatial correlations, suggesting causal connections between the PKG, HDAC, PARP and calpain activities and neuronal cell death. Using different pharmacological and genetic manipulations, causality could indeed be demonstrated. Surprisingly, the often dramatic rises in metabolic activities were not matched by corresponding increases in expression, high-lighting the importance of analyses of protein activities at the cellular level. The above mentioned studies identified a number of metabolic processes previously unknown to be involved in inherited retinal degeneration. Comparing different animal retinal degeneration models uncovered striking similarities in enzymatic activities, suggesting a generality of the destructive pathways. Taken together, these findings provided a number of novel targets for neuroprotection and as such opened up new perspectives for the therapy of hereditary neurodegeneration in the retina and possibly other parts of the central nervous system


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Article Details

Volume: 21
First Page: 1
Last Page: 1
Page Count: 1
DOI: 10.2174/0929867321666140601201337
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