HSPB8 AND NEUROPATHY

Role of the HspB8/Bag3 chaperone complex in neurodegenerative disorders

 Coordinatore ACADEMISCH ZIEKENHUIS GRONINGEN 

 Organization address address: Hanzeplein 1
city: GRONINGEN
postcode: 9713 GZ

contact info
Titolo: Dr.
Nome: P.G.
Cognome: Braun
Email: send email
Telefono: +31 50 3637119
Fax: +31 50 3632612

 Nazionalità Coordinatore Netherlands [NL]
 Totale costo 75˙000 €
 EC contributo 75˙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-IRG-2008
 Funding Scheme MC-IRG
 Anno di inizio 2009
 Periodo (anno-mese-giorno) 2009-05-15   -   2012-05-14

 Partecipanti

# participant  country  role  EC contrib. [€] 
1    ACADEMISCH ZIEKENHUIS GRONINGEN

 Organization address address: Hanzeplein 1
city: GRONINGEN
postcode: 9713 GZ

contact info
Titolo: Dr.
Nome: P.G.
Cognome: Braun
Email: send email
Telefono: +31 50 3637119
Fax: +31 50 3632612

NL (GRONINGEN) coordinator 75˙000.00

Mappa


 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

us    proteins    scas    protein    toxic    cells    protect    autophagy    bag    encoding    neuropathies    drosophila    peripheral    related    disease    spinocerebellar    members    cell    vivo    prevent    hsp    function    family    cope    disorders    hd    chaperones    overexpression    diseases    mutated    genes    aggregation    huntington    misfolded    influence    sca    alpha    upregulation    mutations    degradation    ataxias    progression    molecular    chaperone    found    eif    neuropathy    neuronal    data    actions    orthologue    stimulating    suggest    muscular    hspb   

 Obiettivo del progetto (Objective)

'Molecular chaperones and degradation systems allow cells to cope with misfolded and genetically mutated proteins. The Hsp70/Hsp40 families and the members of the HspB family (HspB1-HspB10) recognize and bind misfolded proteins, prevent their aggregation and facilitate their degradation. Mutations in genes encoding several HspB proteins have been associated with neurological and muscular disorders, strongly supporting a critical role for these proteins in neuronal and muscular cell viability. For this project, we focus on HspB8, which is mutated in peripheral neuropathies. However the precise mechanisms leading to disease progression are largely unknown. Inversely, I found that upregulation of HspB8 in cell systems can ameliorate toxic aggregation of proteins related to polyglutamine diseases, like Huntington disease (HD) or Spinocerebellar ataxias (SCAs). Our data suggest that HspB8 plays a role in autophagy, which deregulation may contribute to neurodegeneration and which upregulation may explain its effects on HD and SCA. In these actions, I found that HspB8 cooperates in a non-canonical manner with Bag3, independent of its classical interaction partners Hsp70 and Bcl-2. I will further analyse connections of HspB8/Bag3 with other HspB members and how they influence autophagy using different in vitro approaches. Recently, we also identified the Drosophila HspB8 orthologue and show that it interacts with Starvin, the Drosophila Bag3 orthologue. This will allow us to evaluate the effects of the complex in vivo and to establish whether the progression of peripheral neuropathies is due to a toxic gain of function (overexpression of mutated HspB8) or to a loss of the HspB8 chaperone activity (knock-out of HspB8) and whether deregulated autophagy is involved in the development of the disease. Finally, crossing our strains with Drosophila models of HD and SCA will allow us establishing whether overexpression of the complex can also inhibit HD or SCA progression.'

Introduzione (Teaser)

The bundling of misfolded proteins is a major characteristic of many degenerative diseases. Autophagy can help offset this aggregation of mutated proteins.

Descrizione progetto (Article)

Molecular chaperones can be employed to identify and attach to misfolded proteins so as to prevent their accumulation. A degradation mechanism can be set in motion by stimulating autophagy. This helps cells cope with misfolded proteins and ensure neuronal survival.

HspB is one such family of molecular chaperones. HspB1-HspB10 members are known to facilitate the degradation of misfolded proteins. Genetic mutations in genes encoding some of these are linked to neuropathies and myopathies. This suggests that they play a major role in the life cycle of neuronal and muscular cells.

The 'Role of the HspB8/Bag3 chaperone complex in neurodegenerative disorders' (HspB8 and neuropathy) project is studying HspB8. Although it is known to be mutated in peripheral neuropathies, the exact processes that lead to development of disease are still unclear.

Prior research has shown that upregulation of HspB8 in cell systems can ease toxic protein aggregation, which is related to diseases such as Huntington's (HD) or spinocerebellar ataxias (SCAs). The main aim of this project is to discover whether alterations brought about in the functioning of the HSPB8-BAG3 chaperone complex can serve to protect against these kinds of disorders.

Data suggest that overexpressing HSPB8-BAG3 can prevent aggregation and facilitate degradation by stimulating autophagy. In these actions, HspB8 forms a stable complex with the co-chaperone BAG3. In other studies done so far, the team has successfully identified the dynamics of HSPB8-BAG3, autophagy and the eIF2 alpha pathway. Results showed that inhibition of the regulation of protein function at the eIF2alpha level can fully annul the effects of HSPB8-BAG3 on autophagy.

Other in vivo studies using a cell model of different mutants revealed that overexpression of human HSPB8 weakens aggregation activity and can protect against degeneration.

HspB8 and neuropathy partners continue to work towards a comprehensive description of how the HSPB8-BAG3 complex can be used to influence the control of protein quality and autophagy. Successes in this area promise to enhance understanding of how HSPB8 mutations lead to peripheral neuropathies.

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