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Content archived on 2024-06-18

Role of sphingolipids in white matter dysfunction in Huntington's disease

Objective

Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a CAG repeat, within the gene encoding huntingtin (Htt) and characterized by the progressive neurodegeneration and associated motor, cognitive and behavioral disturbances. Mutant Htt exerts adverse effects in neurons and non-neuronal cells. Animal studies describe white matter segmentation and myelin breakdown in HD. These evidences recapitulate the brain white matter volume loss described in pre-symptomatic and symptomatic subjects suggesting that white matter dysfunctions may represent a critical determinant in HD pathogenesis and may be identified as an early event of the disease.
Recently, the applicant indentified a new dysfunctional pathway in HD, the dysregulation of ganglioside metabolism. High levels of gangliosides, in particular GM1, have been found to localize also in the myelin sheaths of oligodendrocytes where they play a crucial role in the maintenance of myelin integrity and in the regulation of axon–glia interactions. The applicant demonstrated that levels of GM1 are decreased in HD models and in fibroblasts from HD patients, contributing to heighten HD cells susceptibility to apoptosis. Importantly, administration of GM1 restored ganglioside levels and induced protective effects in HD models suggesting a therapeutic potential of GM1 in CNS. Our hypothesis is that decreased levels of GM1 may also affect white matter homeostasis. Interestingly, no studies correlating the dysregulation in gangliosides metabolism with white matter defects in HD have been conducted, so far. Thus, the main goal of this study is to look for white matter abnormalities and to determine the relationship with the degree of ganglioside dysfunctions and the severity of clinical status in HD. This will represent a new and interesting line of investigation in the field of HD and will provide more clear and deep understanding of the molecular mechanisms underlying the pathogenesis of the disease.

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Topic(s)

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Call for proposal

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FP7-PEOPLE-2011-IIF
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Funding Scheme

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MC-IIF - International Incoming Fellowships (IIF)

Coordinator

INSTITUTO NEUROLOGICO MEDITERRANEO NEUROMED SOCIETA PER AZIONI
EU contribution
€ 249 911,60
Address
VIA ATINENSE 18
86077 Pozzilli Is
Italy

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Region
Sud Molise Isernia
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
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Total cost

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