Effects of nanoparticles on structure and function of the cell nucleus: Analysis of nuclear protein aggregation and neurodegeneration.

• Antragstellerin: Professorin Dr. Anna von Mikecz
• Fachliche Zuordnung: Molekulare Biologie und Physiologie von Nerven- und Gliazellen
• Förderung: Förderung von 2011 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 195436142

The exponentially growing application of nanoparticles (NPs) in engineering and biomedicine calls for analysis of their interactions with cells and whole organisms in order to develop sustainable nanotechnologies. We showed previously that silica-NPs induce neurodegenerative phenotypes in cell culture and the nematode Caenorhabditis elegans. In cell culture silica-NPs cause formation of intranuclear protein aggregates. These inclusions form amyloid-like structures and recapitulate exactly polyglutamine-induced protein aggregation that occurs in neurodegenerative disorders such as Huntington's disease. Silica-NPs enabled demonstration that aggregation of endogenous nuclear proteins activates the ubiquitin-proteasome system, and amyloid-like aggregates represent sites of protein degradation. In contrast, titanium dioxide-NPs induce nuclear inclusions which are correlated with genotoxicity rather than altered proteostasis. Based on these results the main aim of the proposed project is to study the consequences of intranuclear protein aggregation for nuclear function. To this end, biochemical properties of NP-induced aggregates will be analysed in correlation with processes such as replication, DNA damage, repair, transcription, and cell death. Aggregate profiling in correlation with nuclear function seeks to fill the existing gap of knowledge between formation of intranuclear inclusions, resulting aberrant protein-protein interactions and altered function in the nucleus as well as their role in neurodegeneration. The latter will be reinforced by in vivo analyses in Caenorhabditis elegans. Here, the questions will be addressed which neurons and neuroendocrine signalling pathways are targeted in silica-NP-induced defects of egg-laying, and if altered proteostasis and protein aggregation contributes to the malfunction of the egg-laying circuit, e.g. interaction between HSN neurons and vulval muscles. The expected findings are capable to promote both, a better understanding of the role of protein aggregation in neurodegenerative processes, and cellular interactions of NPs.

• DFG-Verfahren: Sachbeihilfen