Translational Medicine - Posters O
Balázs Kis1,2, Anna Abbas1,2, Lea Danics1,2, Anikó Göblös3, Roger A. Barker4, Johan Jakobsson5, Lajos Kemény3,6, Karolina Pircs1,2,5
1 HCEMM-SU, Neurobiology and Neurodegenerative Diseases Research Group, Budapest, Hungary.
2 Institute of Translational Medicine, Semmelweis University, Budapest, Hungary.
3 Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
4 Wellcome-MRC Cambridge Stem Cell Institute & John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
5 Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, Sweden.
6 HCEMM-USZ Skin Research Group, Szeged, Hungary
Huntington’s disease (HD) is an autosomal dominant age-related neurodegenerative disorder caused by a mutated Huntingtin (HTT) gene containing an abnormal number of CAG repeats. Several studies documented altered autophagy in neurodegenerative disorders. Autophagy is an evolutionarily conserved lysosomal degradation pathway that ensures the cytoplasmic homeostasis. Our previous results using an induced neuronal (iN) model showed a subcellular cell type specific alteration of autophagy in HD-derived iNs. Moreover, mass spectrometry identified protein dysregulation in the AMPK pathway, which directly regulates the autophagy pathway.
In this project we will use an iN model to target the AMPK pathway in HD-iNs. We will use an all-in-one self-inactivating lentivirus to directly reprogram donor fibroblasts into neurons. The advantage of this methodology is that iNs maintain age and disease-related signatures of the donor cells as direct reprogramming bypasses the intermediary cell rejuvenation step inevitable in other approaches such as iPSC.
We will perform a mini drug screening with various drugs affecting the AMPK pathway using 5 Ctrl and 5 HD patient derived iNs. We will use high content automated screening microscopy to monitor the neuronal morphology and the expression of different autophagy markers after different drug treatments. We will continue to preclinically validate the best candidates that could rescue some key aspects of the disease phenotype presented in HD-iNs.
After careful pre-clinical validation of the best autophagy targeting hits, this proposal holds great potential to develop novel and better drugs specifically targeting components of the autophagic pathway firstly for HD, and later for other neurodegenerative proteinopathies (like Alzheimer’s diseases, Parkinson’s diseases and Frontotemporal dementia).