Team Name: ‘Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases’

Link to team page: www.cattaneolab.it

Institute: Department of Bioscience, University of Milan and Istituto Nazionale Genetica Molecolare – INGM - ´Romeo ed Enrica Invernizzi, Milan, Italy

Address: Padiglione Invernizzi, Via Francesco Sforza 35, 20122 Milano – ITALY

Description of research

The laboratory aims at exploiting the recent advances in embryonic and induced stem cell biology to obtain the medium-sized spiny striatal neurons that degenerate in HD. These would represent an important tool for disease modelling and to study early pathogenic events. On the other hand, the lab is heavily involved in the study of the molecular mechanisms underlying neuronal cell loss as a consequence of the mutation in the HD gene and has identified a number of molecular pathways targeted by the mutant gene. In a parallel approach the lab is pursuing a detailed characterization of the function and evolution of the normal gene. The lab’s ultimate goal is to identify cells, molecules and pathways that are suitable for therapeutic intervention and new reagents for drug screening in Huntington´s Disease.

Among these years, the lab produced more than 160 papers, with a total h-index of 54. The lab scientific achievements include:

1. Showing evidence that the CAG repeat in the huntingtin gene is present during evolution and it is connected with neural development (Tartari et al., Mol Biol and Evolution, 2008; Lo Sardo V., Zuccato C. et al., Nature Neuroscience, 2012)

2. Finding that, in the adult brain, normal huntingtin gene is a neuroprotective factor and stimulates the production of BDNF (Rigamonti et al., The Journal of Neuroscience, 2000; Zuccato et al. Science, 2001; Zuccato et al., Nature Genetics, 2003)

3. Providing evidence that mutated Huntington´s gene causes alterations in the transcription of genes controlled by REST/NRSF factor, including BDNF (Zuccato et al., The Journal of Neuroscience, 2007; Conforti et al., Gene Therapy, 2012)

4. Showing that the mutation alters the functionality of cholesterol biosynthesis in the nervous system in cells, animals and patients (Valenza et al., The Journal of Neuroscience, 2005; Leoni et al., Brain 2008; Valenza et al., The Journal of Neuroscience, 2010)

5. Producing iPS cells reprogrammed from Huntington´s disease patients as a model for screening (Camnasio S., Delli Carri A. et al., Neurobiology of Disease, 2012; Mattis et al., Cell Stem Cell, 2012 Consortium Paper)

6. Developing protocols to differentiate human pluripotent stem cells into striatal neurons which degenerate in Huntington´s disease (Goffredo, Cell Death and Differentiation, 2008; Onorati et al., Cell Mol Life Science, 2011; Conforti et al., Neurobiology of Disease, 2013; Delli Carri A., Onorati M. et al., Development, 2013).

7. Reconstructing the molecular profile and transcription factors coexpression that qualify human fetal striatal neurons development in vivo (Onorati et al., Nature Neuroscience, 2014).

Research to be done in the context of Circprot

Based on its expertise in human pluripotent stem cell neural differentiation, Partner 8 will set up efficient protocols for the generation of MSNs and will collaborate with other Partners for the analyses of BDNF/TrkB signalling networks that crucially control synaptic plasticity, leading to spine loss in HD. Specifically, UMIL will provide Partner 1 (Lessmann) and Partner 5 (Saudou) with fully characterized differentiated MSNs, carrying different numbers of CAG repeats, aiming at investigate BDNF expression/trafficking parameters by highly innovative microfluidic approaches to isolate axons from cell bodies and follow fluorescently-tagged BDNF trafficking in either pre- or postsynaptic neurons. Furthermore, UMIL will also focus on mechanisms of optimization of BDNF/TrkB signaling networks as endogenous protective factors against HD, aiming at restore the cortical axon and striatal dendritic defects in HD. To this purpose, proteome/interactome changes will be evaluated together with Partner 2 (Castren) on drugs-treated cultured HD neurons, in order to evaluate their capability to enhance BDNF expression or mimick specific aspects of TrkB downstream signaling.

 

 

 

Key publications

Faedo A. et al.,  (2017) Differentiation of human telencephalic progenitor cells into MSNs by inducible expression of Gsx2 and Ebf1.Proceedings of the National Academy of Sciences USA. epub ahead of print

Valenza M. et al., (2015) Cholesterol-loaded nanoparticles ameliorate synaptic and cognitive function in Huntington´s disease mice. EMBO Molecular Medicine, 7(12), 1547-1564

Onorati M. et al., (2014) Molecular and functional definition of the developing human striatum. Nature Neuroscience; (12):1804-15

Delli Carri A. et al., (2013) Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation towards fully functional DARPP-32 medium-sized spiny neurons. Development, 140, 301-312

Lo Sardo V. et al., (2012) An evolutionary recent neuroepithelial cell adhesion function of huntingtin implicates ADAM10-Ncadherin. Nature Neuroscience, 15, 713-21

The HD iPSC Consortium, (2012) Induced Pluripotent Stem Cells from Patients with Huntington´s Disease: Show CAG Repeat-Expansion-Associated Phenotypes. Cell Stem Cell, 2, 264-278