Role of nucleolar stress in the progression of neurodegeneration in models of Huntington´s disease.

• Applicant: Dr. Rosanna Parlato
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 253776045

The nucleolus not only regulates rRNA synthesis and ribosome biogenesis but also the response to cellular stress. Neurodegenerative diseases such Parkinson´s (PD) and Huntington´s disease (HD) are linked to nucleolar disruption and impaired rRNA transcription. The role of nucleolar stress in the nervous system has not been systematically explored. Mutant mice characterized by impaired nucleolar activity in dopaminergic neurons that are affected in PD, show mitochondrial and oxidative damage and slowly progressive neurodegeneration, typical of the degenerative process in the human disease. However the slow progression also suggests that mechanisms against nucleolar and oxidative stress prolong neuronal survival. These neuroprotective mechanisms may involve downregulation of the mammalian target of rapamycin (mTOR) and induction of autophagy as in dopaminoceptive neurons of the striatum. These neurons are mainly affected in HD, a fatal inherited disorder in the huntingtin gene leading primarily to impaired control of voluntary movements. However the molecular mechanisms by which mutant huntingtin (mHtt) causes neuronal death are still poorly understood. Interestingly, rRNA transcription is strongly downregulated by mHtt at early stages, suggesting a critical role in the progression of HD. Mouse models of impaired rRNA synthesis in striatal neurons enable to dissect the mechanisms responding to nucleolar stress in this context. Interestingly, by mRNA expression profiling prior to neuronal death we found significant similarities between the transcriptional changes triggered by inhibited nucleolar activity and those detected in mouse model and human HD.In this proposal we will investigate the mechanisms responsible for the neuronal vulnerability to stress-induced damage dependent on rRNA deficits and mHtt. In particular we will study whether nucleolar stress accelerates or it temporarily delays HD progression by transient beneficial effects in HD models. To this end, we will mimic nucleolar stress in HD models by genetic ablation of the transcription factor TIF-IA essential for regulating RNA polymerase I activity depending on permissive or deleterious conditions. By biochemical, histological and behavioral analysis we will identify the role of increased nucleolar stress in the function and survival of striatal neurons and characterize its the impact on protein synthesis, autophagy and mitochondrial function in HD models. By mRNA expression profiling at a stage prior to neuronal death we identified genes that could play a role in the response to nucleolar stress. By downregulation and overexpression experiments in neuronal models of HD we will analyze the function of selected genes that could regulate nucleolar stress responses and neuronal survival.This research will expand our knowledge of factors modifying disease progression in response to dysregulated cellular homeostasis in HD and possibly in other neurodegenerative disorders.

• DFG Programme: Research Grants