RESEARCH

Introduction

Our laboratory studies Huntington’s disease – a rare genetic and neurodegenerative disease. We have been researching this area for more than 20 years. Our goal is to contribute to the understanding of the physiopathology of this disease and to develop pharmacological, genetic and cellular strategies that could slow down the course of the illness or prevent its onset.

RESEARCH ACTIVITIES

Our research has two strategies:
1. We study the healthy huntingtin gene, its evolution and physiological role in brain tissue, and analyse the specific molecular changes that may be activated by the ill gene.
2. We develop approaches that make use of pluripotent stem cells (embryonic and reprogrammed) and human neural stem cells to produce the specific neurons that die during the illness. These cellular systems may also prove useful in molecular and pharmacological screening strategies and in experimental grafting in the brain.

Our work combines these two strategies to study the mechanisms of Huntington’s disease and intervention schemes in human neurons obtained from pluripotent stem cells. The laboratory works with Huntington’s disease clinical experts in Italy and abroad, to assess the diagnostic and therapeutic potential of our research findings for clinical translation and application.

The lab’s scientific achievements include:

a.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)
b.Finding that, in the adult brain, non mutated huntingtin gene is a neuroprotective factor and stimulates the production of the BDNF neurotrophic factor (Rigamonti et al., The Journal of Neuroscience, 2000; Zuccato et al. Science, 2001; Zuccato et al., Nature Genetics, 2003)
c.Providing evidence that mutated huntington’s gene causes alterations in the transcription of genes controlled by REST/NRSF factor, including BDNF gene (Zuccato et al., The Journal of Neuroscience, 2007; Conforti et al., Gene Therapy, 2012)
d. 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)
e. 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)
f. Generating neural stem cells able to differentiate into striatal neurons which later 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)

Reviews by our lab include:

Cattaneo et al., “Normal huntingtin function: an alternative approach to HD”, Nature Reviews Neuroscience, 2005

Zuccato C., Cattaneo E., “Brain derived neurotrophic factor in HD”, Nature Reviews Neurology, 2009

Conti L., Cattaneo E., “Neural stem cell systems: physiological players or in vitro entities?”, Nature Reviews Neuroscience, 2010

Zuccato et al., “Molecular mechanisms and potential therapeutical targets in HD”, Physiological Reviews, 2010

Valenza M., Cattaneo E., “Emerging roles for cholesterol in HD”, Trends in Neurosciences, 2011

Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases