RP7: Investigation of novel mechanisms in degradation of aggregated neuroserpin

点击翻译按钮获取中文摘要

Neuronal accumulation of mal-processed proteins is the hallmark of a number of neurodegenerative disorders such as diffuse Lewy body diseases, tauopathies and familial encephalopathy with neuroserpin inclusion bodies (FENIB). Some of these diseases share common pathways leading to neuronal death, which are linked to accumulation of proteins in specific intracellular compartments. Accumulation of malprocessed neuroserpin reflects a dynamic process, resulting from the disturbed balance between synthesis and degradation. During the first funding period we were able to recapitulate the pathogenic characteristics such as aggregation, degradation, and neurodegeneration in a mouse model for FENIB.The objective of our proposal is to identify components involved in the degradation of aggregated neuronal proteins. We have generated a Caenorhabditis elegans model for FENIB by expressing fluorescently tagged, aggregation-prone forms of the neuroserpin homolog SRP-2. This model allows us to screen for novel modulators and pharmalogical substances modulating the degradation of aggregated SRP-2, which will be further investigated in mammalian cell culture experiments and transgenic neuroserpin expressing mice. Data from these studies will be valuable in identifying novel therapeutical strategies for dementias in general.