Background and Purpose - The aggregation of misfolded, mutated proteins (SOD1, TDP-43) is a pathological hallmark of the familial forms of Amyotrophic Lateral Sclerosis (ALS). Cells have evolved an elaborate protein quality control system mediated by molecular chaperones, in order to facilitate folding/refolding of these misfolded species that can exert neurotoxicity. When folding is unsuccessful, chaperones can also target the misfolded proteins for degradation, thereby preventing protein aggregation. Intracellular degradation is primarily mediated by two proteolytic systems: the ubiquitin proteasome system and autophagy , and a proper balance and cross-talk between them is required for normal protein homeostasis, while their alteration may contribute to ageing and disease [2,3]. We already published that overexpression of the small heat shock protein HSPB8 (and its partner Bag3) in motoneuron cells (NSC34) prevents aggregation of mutated SOD1 and TDP-43, by either directly targeting them to the autophagic vacuoles for degradation and/or restoring/boosting the autophagy flux [4,5]. Moreover our recent data indicate that BAG3 upregulation, following proteasome inhibition, significantly contributes to the compensatory activation of autophagy and to the re-routing of (poly)ubiquitinated proteins to autophagy for degradation. Motoneurons are particularly sensitive to misfolded protein toxicity, but also other cell types could be affected. As an example, muscle-restricted expression of the mutSOD1, results in muscle atrophy associated with motoneuron death. Methods and Results - We compared the potential mutSOD1 toxicity in motoneuron (NSC34) and muscle (C2C12) cells, and found that muscle ALS models possess much higher proteasome activity and autophagic power than motoneuron ALS models, which allow to better cope with misfolded protein aggregation . The same results were also obtained with mutTDP43. These findings were further confirmed analyzing the expression of the LC3 and p62 genes (two well known autophagic markers) as well as of BAG3 and HSPB8 genes, which after proteasome inhibition are all higher activated in muscle cells than motoneuron cells. Finally we also found that the knock-down of HSPB8 increases the aggregation of both wt and mutTDP43 in C2C12, but only of mutTDP43 in NSC34, suggesting that HSPB8 plays a primary role in TDP43 turn-over especially in muscle cells. Conclusions - These data together with the observation that HSPB8 and BAG3 are upregulated in muscles of ALS transgenic mice only at symptomatic stage and that HSPB8 is upregulated in surviving motor neurons in transgenic ALS mice during disease progression, strongly suggest that the boosting of this complex may serve to clear aggregates in chronic neurodegenerative diseases. References  Rubinsztein DC. 2006. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443:780-786.  Gamerdinger M, Hajieva P, Kaya AM, Wolfrum U, Hartl FU, Behl C. 2009. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. Embo J 28:889-901.  Morimoto RI. 2008. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev 22:1427-1438.  Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E, Galbiati M, Fontana E, Marino M, Carra S, Bendotti C, De Biasi S, Poletti A. 2010. The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS). Human molecular genetics 19:3440-3456.  Carra S, Crippa V, Rusmini P, Boncoraglio A, Minoia M, Giorgetti E, Kampinga HH, Poletti A. 2011. Alteration of protein folding and degradation in motor neuron diseases: Implications and protective functions of small heat shock proteins. Prog Neurobiol 97:83-100.  Onesto E, Rusmini P, Crippa V, Ferri N, Zito A, Galbiati M, Poletti A. 2011. Muscle cells and motoneurons differentially remove mutant SOD1 causing familial amyotrophic lateral sclerosis. Journal of Neurochemistry 118: 266–280.
The role of the HSPB8-BAG3 complex in age-related protein misfolding diseases / A. Boncoraglio, E. Onesto, V. Crippa , P. Rusmini, E. Giorgetti, R. Cristofani, M. Minoia, H.H. Kampinga, S. Carra, A. Poletti. ((Intervento presentato al convegno Next Step 4 La giovane ricerca vanza tenutosi a Milano nel 2013.
|Titolo:||The role of the HSPB8-BAG3 complex in age-related protein misfolding diseases|
|Data di pubblicazione:||17-lug-2013|
|Settore Scientifico Disciplinare:||Settore BIO/13 - Biologia Applicata|
|Citazione:||The role of the HSPB8-BAG3 complex in age-related protein misfolding diseases / A. Boncoraglio, E. Onesto, V. Crippa , P. Rusmini, E. Giorgetti, R. Cristofani, M. Minoia, H.H. Kampinga, S. Carra, A. Poletti. ((Intervento presentato al convegno Next Step 4 La giovane ricerca vanza tenutosi a Milano nel 2013.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|