Transkriptomanalyse und -validierung neuroprotektiver Kandidaten zur Entwicklung neuer diagnostischer und therapeutischer Ansätze in der Neurologie
Molekulare und zelluläre Neurologie und Neuropathologie
Zusammenfassung der Projektergebnisse
Despite the breathtaking advances in biomedical research over the past decades, the majority of both acute and chronic disorders of the central nervous system (CNS) cannot be treated in a curative or causal fashion. Importantly, most neurological diseases share one striking similarity: the death of neuronal cells is what produces often long-lasting malfunctions and symptoms in affected individuals. However, little is currently known about the exact molecular mechanisms that take place in neurons after injury or damage leading to cell death. Thus, the main goal of this project was to explore whether fundamental cellular pathways exist within damaged neurons that transduce different stress types to produce a common response of neurons to cell injury. To identify the transcriptional signature of neurons to stress, we used transcriptional profiling (RNA-Seq) of cultured primary mouse neurons. In order to determine which of these genes are not only transcriptionally responsive to cell injury but also functionally important with regard to stress in an in vivo model, we deployed the genetically tractable model C. elegans for validation. By this means, we identified 7 genes are (i) transcriptionally regulated by neuronal injury, (ii) have no previously known role in the cellular stress response, (iii) are evolutionarily conserved from C. elegans to humans, and (iv) have a validated relevance for the survival of neurons in vivo. Among those novel and conserved stress-responsive genes, we found that the metabolic enzyme GDPGP1/mcp-1 is transcriptionally down-regulated in neurons across species, in response to a variety of stresses. Functionally, GDPGP1/mcp-1 protects against stress. Knockdown of GDPGP1 in mouse neurons leads to widespread neuronal cell death. Loss of mcp-1, the single homologue of GDPGP1 in C. elegans, leads to neurodegeneration as well as reduced survival of animals following environmental stress. Over-expression of mcp-1 in neurons enhances survival under hypoxia and protects against neurodegeneration in a tauopathy model. We therefore postulate that down-regulation of GDPGP1/mcp-1 during cell injury is a maladaptive neuronal response, present from C. elegans to mouse, that limits the viability of neurons under stress.
Projektbezogene Publikationen (Auswahl)
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The stress-responsive gene GDPGP1/mcp-1 regulates glycogen metabolism and survival of neurons. J Cell Biol. 2020 Feb 3;219(2)
Schulz, Alexander; Sekine, Yuichi; Oyeyemi, Motunrayo J.; Abrams, Alexander J.; Basavaraju, Manasa; Han, Sung Min; Groth, Marco; Morrison, Helen; Strittmatter, Stephen M. & Hammarlund, Marc
