We use a multidisciplinary approach to study Huntington's disease (HD), one of the most common inherited neurodegenerative disorders. HD is due to the expansion of a polyglutamine stretch in a protein named huntingtin. Similar to Alzheimer and Parkinson, HD causes specific neurons to die, leading to motor and cognitive dysfunction.
The exact mechanism by which neurodegeneration occurs in HD is poorly understood. Before dying, HD neurons displays a wide array of cell dysfunctions, including aberrant cell signaling and neurotransmission, dysregulation of gene expression and impaired mitochondrial metabolism.
Our goal is to elucidate the cellular and molecular mechanisms responsible for neuronal dysfunction and death in HD, and to identify potential treatments for this devastating disease.
Main research projects:
1. Lipids and HD.
HD neurons have impaired synthesis of cholesterol and gangliosides, lipid molecules that are highly enriched in the brain. Both cholesterol and gangliosides are important components of membrane micro-domains that serve as hubs for cell signaling, and are crucial for many brain functions. Therefore, decreased synthesis of these lipids is likely to have profound effects on HD pathogenesis. We study the role of cholesterol and gangliosides in cell signaling defects and in cell death in HD, as well as their effects on motor and cognitive behavior in transgenic HD mouse models, and their potential therapeutic use.
2. Mutant huntingtin and the transcription of cholesterogenic genes.
We study the transcription factors that regulate the expression of lipid-related genes, and how they work in normal and HD cells.
3. Post-translational modifications of mutant huntingtin toxicity.
Recent studies suggest that the intracellular localization, function and toxicity of mutant huntingtin can be regulated by post-translational protein modifications such as phosphorylation, ubiquitination and others. We are interested in understanding how neuroprotective post-translational modifications of huntingtin are triggered, in order to identify novel therapeutic targets.
Mejia EM, Chau S, Sparagna GC, Sipione S and Hatch GM. (2016) Reduced Mitochondrial Function in Human Huntington Disease Lymphoblasts is Not Due to Alterations in Cardiolipin Metabolism or Mitochondrial Supercomplex Assembly. Lipids [ePub ahead of print]. PMID: 26846325.
Weishaupt N, Mason AL O, Hurd C, May Z, Zmyslowski DC, Galleguillos D, Sipione S, and Fouad K. (2014) Vector-induced NT-3 expression in rats promotes collateral growth of injured corticospinal tract axons far rostral to a spinal cord injury. Neuroscience. 272:65-75. PMID: 24814724.
Weishaupt N, Li S, Di Pardo A, Sipione S, Fouad K. (2013) Synergistic effects of BDNF and rehabilitative training on recovery after cervical spinal cord injury. Behav Brain Res 239:31-42. PMID: 23131414.
Lian J, Wei E, Wang S, Quiroga A, Li L, Di Pardo A, van der Veen J, Sipione S, Mitchell G, Lehner R.(2012) Liver specific inactivation of carboxylesterase 3/triacylglycerol hydrolase decreases blood lipids without causing severe steatosis. Hepatology 56(6):2154-2162 PMID: 22707181.
Mohamed A, Saavedra L, Di Pardo A, Sipione S, Posse de Chaves E.(2012) B-Amyloid Inhibits Protein Prenylation and Induces Cholesterol Sequestration by Impairing SREBP-2 Cleavage. J Neurosci. 32(19), 6490-6500. PMID: 22573671.
Di Pardo A, Maglione V, Alpaugh M, Horkey M, Atwal RS, Sassone J, Ciammola A, Steffan JS, Fouad K, Truant R, Sipione S. (2012) Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores motor behavior in Huntington disease mice. Proc Natl Acad Sci USA, 109(9), 3528-33. PMID: 22331905.
Atwal RS, Desmond DR, Caron N, Maiuri T, Xia J, Sipione S, Truant R. (2011) Kinase inhibitors modulate huntingtin cell localization and toxicity. Nature Chem. Biol., 7(7), 453-60. PMID: 22331905.
Battaglia G, Cannella M, Riozzi B, Orobello S, Maat-Schieman ML, Aronica E, Busceti CL, Ciarmiello A, Alberti S, Amico E, Sassone J, Sipione S, Bruno V, Frati L, Nicoletti F, & Squitieri F. (2011) Early defect of transforming growth factor beta-1 formation in Huntington's disease. J Cell Mol Med. 15, 555-571. PMID: 20082658.
Maglione V, Marchi P, Di Pardo A, Lingrell S, Horkey M, Tidmarsh E. & Sipione S. (2010) Impaired ganglioside metabolism in Huntington's disease and neuroprotective role of GM1. J Neurosci. 17, 4072-80. PMID: 20237277.
Sassone J, Colciago C, Marchi P, Ascardi C, Alberti L, Di Pardo A, Zippel R, Sipione S, Silani V. & Ciammola A. (2010) Mutant huntingtin induces activation of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNip3). Cell Death & Disease 1:e7. PMID: 21364626.
Posse de Chaves E, & Sipione S. (2010) Sphingolipids and gangliosides of the nervous system in membrane function and dysfunction. FEBS Lett. 584, 1748-59. PMID: 20006608.