Pharmacology

Simonetta Sipione

Dr Simonetta Sipione

Associate Professor

Education:
BSc Biological Sciences, University of Catania (Italy)
PhD Biochemistry, University of Catania (Italy)

Teaching: PMCOL 412*, NEURO451/452* NEURO410/510, BIOCH455/555, PHARM417, CELL505

Website: sipionelab.org

Research: Molecular mechanisms in neurodegeneration

Research Interests / Laboratory Techniques

1) Role of gangliosides in neurodegeneration, neuroinflammation and neuroprotection

Gangliosides are glycolipids highly enriched in the brain, with crucial functions in cell signaling, immune-modulation and cell-cell interactions. Loss of function mutations in genes that encode ganglioside biosynthetic enzymes result in early-onset neurodegenerative diseases. Decreased levels of gangliosides and/or changes in ganglioside profile (i.e. in the relative abundance of specific gangliosides) have been reported also in common neurodegenerative disorders such as Parkinson disease (PD), Alzheimer disease (AD) and Huntington’s disease (HD).

We investigate the function of gangliosides in the communication between brain cells and in neuroinflammation, to find treatments for diseases caused by lack of gangliosides, and to harness gangliosides’ neuroprotective properties for the treatment of neurodegenerative and neuroinflammatory diseases.

2) Molecular mechanisms of neurodegeneration in Huntington’s disease
We use a multidisciplinary approach to study Huntington's disease (HD), one of the most common inherited neurodegenerative disorders, characterized by motor, cognitive and psychiatric symptoms. HD is due to the expansion of a polyglutamine stretch in a protein named huntingtin. This mutation results in mutant huntingtin misfolding and aggregation, followed by neuronal dysfunction and neurodegeneration.

We have discovered that the synthesis of gangliosides is impaired in HD cells, leading to lower levels than normal of GM1 and other gangliosides. Using cell and animal models of the disease, as well as biological samples from patients, we investigate the consequences of ganglioside reduction on disease pathogenesis and progression, and the potential role gangliosides as biomarkers of HD progression.

We have also shown that administration of ganglioside GM1 has profound therapeutic and disease-modifying effects in animal models of HD. We use a variety of biochemistry, cell biology and proteomics approaches, in vitro and in vivo, to identify the underlying mechanisms and to develop ganglioside-based therapies for HD.

Selected Recent Publications

Baronas VA, Yang RY, Morales LC, Sipione S, Kurata HT. Slc7a5 modifies the functional outcome of epilepsy-linked Kv1.2 channel mutations. Nature Commun., 9(1):4417

 

Bowie LE, Maiuri T, Alpaugh M, Gabriel M, Arbez N, Galleguillos D, Hung CLK, Patel S, Xia J, Hertz NT, Ross CA, Litchfield DW, Sipione S, Truant R (2018) N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation. Proc. Natl. Acad. Sci. USA, 115(30):E7081-E7090.

 

Alpaugh M, Galleguillos D, Forero J, Morales LC, Lackey SW, Kar P, Di Pardo A, Holt A, Kerr B, Todd KG, Baker GB, Fouad K and Sipione S (2017) Disease-modifying effects of ganglioside GM1 in Huntington’s disease models. EMBO Mol. Med., 9 (11):1537-1557

Han L, Morales LC, Richards MR, Kitova EN, Sipione S, Klassen JS (2017) Investigating the influence of membrane composition on protein-glycolipid binding using nanodiscs and proxy ligand electrospray ionization mass spectrometry. Anal Chem., Sep 5;89(17):9330-38.

Wei D, Hurd C, Galleguillos D, Singh J, Fenrich KK, Webber CA, Sipione S, Fouad K (2016) Inhibiting cortical protein kinase A in spinal cord injured rats enhances efficacy of rehabilitative training. Exp Neurol., 283(Pt A):365-74.

Mejia EM, Chau S, Sparagna GC, Sipione S and Hatch GM (2016) Reduced mitochondrial function in Huntington disease lymphoblasts is not due to alteration in cardiolipin metabolism or supercomplex assembly. Lipids, 51(5):561-9.

Weishaupt N, Mason AL, Hurd C, May Z, Zmyslowski DC, Galleguillos D, Sipione S, 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. Neurosci., 272:65-75.

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.

Mohamed A, Saavedra L, Di Pardo A, Sipione S, Posse de Chaves E (2012). β-Amyloid Inhibits Protein Prenylation and Induces Cholesterol Sequestration by Impairing SREBP-2 Cleavage. J Neurosci. 9;32(19):6490-500.

Lian j, Wei E, Wang S. Quiroga A, Li L, Di Pardo A, van der Veen J, Sipione S, Mitchell G and Lehner R. (2012) Liver specific inactivation of carboxylesterase 3/triacylglycerol hydrolase decreases blood lipids without causing severe steatosis. Hepatology, 56(6):2154-62.

Di Pardo A, Maglione V, Alpaugh M, Horkey M, Atwal RS, Sassone J, Ciammola A, Steffan JS, Fouad K, Truant R and 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.

Atwal RS, Desmond DR, Caron N, Maiuri T, Xia J, Sipione S and Truant R (2011) Kinase inhibitors modulate huntingtin cell localization and toxicity. Nat. Chem. Biol., 7(7):453-60.

 

Maglione V, Marchi P, Di Pardo A, Lingrell S, Horkey M, Tidmarsh E and Sipione S. (2010) Impaired ganglioside metabolism in Huntington’s disease and neuroprotective role of GM1. J. Neurosci., 17(11):4072-80.