RESEARCH

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Huntington's disease: a domino effect triggered by mutant huntingtin

 

Huntington’s disease (HD) is an inherited neurodegenerative disorder that causes progressive motor and cognitive dysfunction. The disease is caused by the expansion of a polyglutamine (polyQ) stretch in a protein named huntingtin.

Cells in HD brains are profoundly affected at multiple levels, from gene transcription to vesicle trafficking, cell signaling, energy metabolism and mitochondrial and synaptic function. It is not clear how mutant huntingtin affects so many aspects of the cell physiology. Our research focuses on the molecular mechanisms underlying HD with the ultimate goal of identifying therapeutic targets to treat this devastating disorder.

MRI images of brains from a normal subject and a patient with HD
MRI images of brains from a normal subject and a patient with HD

Etiology of HD and mutant huntingtin misfolding
Etiology of HD and mutant huntingtin misfolding

MRI images of brains from a normal subject and a patient with HD
MRI images of brains from a normal subject and a patient with HD

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Gangliosides in brain health and in neurodegeneration

 

Gangliosides are glycosphingolipids (sugar-lipid molecules) highly enriched in the brain. Embedded in cell lipid bilayers, gangliosides modulate the activity of several membrane proteins and growth factor receptors, and play an important role in many cell signalling pathways and in normal brain functioning.

In spite of the large body of evidence that links gangliosides to brain health and diseases, our understanding of the functions of these molecules is still very limited.

Our laboratory and others have shown that a reduction of ganglioside levels occurs in HD and in Parkinson's disease (PD).  Restoring normal GM1 levels protects HD cells from apoptosis, slows down neurodegeneration and restores normal behaviour in HD animal models. Other studies have shown that GM1 is also protective in PD.

We are investigating the underlying molecular mechanisms to uncover novel functions of gangliosides involved in normal cell physiology and neuropathology.

GM1 has therapeutic and disease-modifying effects in HD animal models
GM1 has therapeutic and disease-modifying effects in HD animal models

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PROJECTS

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Fundamental research

Role of gangliosides in proteostasis and clearance of misfolded proteins
We are investigating the role of gangliosides in cellular mechanisms that are involved in the clearance of toxic misfolded proteins (e.g. mutant HTT, alpha-synuclein etc.), including autophagy, unconventional protein secretion and extracellular vesicle biogenesis, and how gangliosides may help decreasing the accumulation of misfolded proteins and protein aggregates in Huntington's disease and other neurodegenerative conditions.
Role of microglia dysfunction in HD and modulatory effects of gangliosides on microglia biology and neuroinflammation
Microglia are the immune cells of the brain and have many functions, including fighting pathogens, repairing damage, remodelling synapses and providing neurotrophic support to neurons. In many neurodegenerative conditions, including HD, microglia become dysfunctional and contribute to create a toxic environment for neurons. We are studying the role of gangliosides as modulators of microglia functions and as anti-inflammatory molecules.
Lipid metabolism dysregulation in HD
Several studies have shown that, along with gangliosides, the synthesis of cholesterol and other lipids is also affected in HD. Cholesterol synthesis is regulated by the transcription factors sterol-regulatory element binding proteins (SREBPs). We are investigating how expression of mutant HTT affects the activity of SREBPs and what are the consequences of lipid dysregulation for HD pathogenesis and progression. 
Development of ganglioside-based therapies for HD
In collaboration with analytical chemists, we are exploring methods for optimal brain delivery of gangliosides and to safely administer ganglioside GM1 in patients.  We are investigating ganglioside molecular features required and sufficient to mediate neuroprotective and anti-inflammatory effects. The overall goal of these studies is to develop therapies that can be used in humans and advance fundamental lab discoveries to the treatment of patients.
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Gangliosides as disease biomarkers in HD
In collaboration with clinician neurologists and analytical chemists, we are studying whether ganglioside levels in the blood and in the cerebrospinal fluid of HD patients correlate with disease severity and progression, and whether gangliosides can be used to predict disease course and response to neuroprotective treatments (biomarkers). We are collaborating with analytical chemists and clinicians to determine whether gangliosides can be used as disease biomarkers in HD.

Clinical & Translational research