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Content archived on 2024-05-29

Dissecting neuronal degeneration: Neuronal ceroid lipofuscinoses from genes to function

Objective

Neuronal ceroid-lipofuscinoses (NCLs) compose the most common type of inherited progressive encephalopathies in children. They are characterized by progressive death of cortical neurons and thus these rare diseases provide an excellent model to characterize molecular events resulting in neuronal degeneration. Using genomic approaches we have identified six out of seven proteins underlying NCLs: PPT1, CLN3, CLN5, CLN6, CLN8, and cathepsin D, the deficiencies of which result in neurodegenerative disorders with clinical features varying from an infantile lethal disease to relatively late onset neuropathological symptoms. Despite identification of these proteins the pathogenetic mechanisms of NCLs remain unclear. The underlying disease mechanisms must, however, be crucial to the survival of neurons. Consequently, this proposal is devoted to reveal the molecular pathways involved in NCL, the final goal being better understanding of the processes resulting in neuronal death. We will generate and use novel models for NCL: cell, yeast, nematode and mouse models at the cellular, tissue and whole organism level. Our first task will be to characterize the individual NCL proteins by studying their intracellular localization, transport and molecular interactions in neuronal cell models. The second task will be to generate and analyze yeast and nematode model organisms, which are extremely well suited for the dissection of the function of conserved NCL-proteins. The third task will be to analyze the pre-existing mouse models, mainly generated by the participants of this proposal, as well as to develop one novel mouse model for NCL. Special emphasis will be laid on the fourth task aiming to use advanced technologies of neuroanatomy and neurophysiology to address the mechanisms of neurodegeneration in these models. The fifth task is to develop bioinformatic tools and to expose putative novel metabolic pathways involved in NCL by gene express...

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Keywords

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Topic(s)

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Call for proposal

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FP6-2002-LIFESCIHEALTH
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Funding Scheme

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STREP - Specific Targeted Research Project

Coordinator

KANSANTERVEYSLAITOS
EU contribution
No data
Address
Mannerheimintie 166
HELSINKI
Finland

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Total cost

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No data

Participants (5)

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