NEURONAL SPECIFICITY

Longitudinal analysis to study neurodegenerative diseases mechanisms in specific neuronal subtypes

Coordinatore	FUNDACION PARA LA INVESTIGACION MEDICA APLICADA FIMA    more  Organization address address: AVENIDA DE PIO XII 55 city: PAMPLONA postcode: 31008 contact info Titolo: Mr. Nome: Fernando Cognome: De La Puente Email: send email Telefono: 34948194700 Fax: 34948194718
Nazionalità Coordinatore	Spain [ES]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2007-4-3-IRG
Funding Scheme	MC-IRG
Anno di inizio	2009
Periodo (anno-mese-giorno)	2009-05-01   -   2013-04-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	FUNDACION PARA LA INVESTIGACION MEDICA APLICADA FIMA  Organization address address: AVENIDA DE PIO XII 55 city: PAMPLONA postcode: 31008 contact info Titolo: Mr. Nome: Fernando Cognome: De La Puente Email: send email Telefono: 34948194700 Fax: 34948194718	ES (PAMPLONA)	coordinator	0.00

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 Obiettivo del progetto (Objective)

'Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) are the most common human neurodegenerative diseases. Each features an abnormal accumulation of proteins, but whether the aggregation leads to neuronal death is controversial. HD is caused by a single mutation that increases the number of CAG repeats. Mutant huntingtin (htt) forms intraneuronal inclusion bodies (IBs). To determine if IBs are pathogenic, incidental, or a beneficial coping response, we developed an automated microscope system that enabled us to follow individual neurons over long periods of time. We prospectively measured the survival time of individual neurons and simultaneously monitored features, such as htt expression levels and IB formation. Using survival analysis methods, we sought to identify the best predictor of neuronal death. We found that the amount of diffuse mutant htt predicted death and that IB formation decreased the risk of neuronal death. Thus, IB formation may be a coping response against the more toxic diffuse mutant htt forms. Another common pathological hallmark of neurodegenerative disorders is a strong specificity for the affected neuronal populations. Paradoxically, the proteins affected in these diseases are ubiquitously expressed and yet only specific subsets of neurons are affected. Interestingly, areas less affected in HD brain patients show more IBs. Because aggregation and neuronal specificity are hallmarks of neurodegenerative diseases, we hypothesize that the different capacities of neuronal subtypes for handling mutant proteins (i.e., efficient aggregation or/and activating degradation pathways) explain differences in survival among neuronal types. We will express proteins affected in htt variants or PD (mutant versions of LRRK2) in different subtypes of primary neurons. Using longitudinal survival, we will determine if aggregation or degradation determines survival or death differentially in particular neuronal subtypes.'