The aggregation of misfolded, mutated proteins (Superoxide-Dismutase-1, SOD1; TAR-DNA-binding-protein-43, TDP-43) is a pathological hallmark of familial forms of Amyotrophic Lateral Sclerosis (ALS), suggesting that the protein quality control system (molecular chaperones and the degradative systems ubiquitin-proteasome and autophagy) is saturated or not sufficient to maintain a correct proteostasis. Motoneurons are particularly sensitive to misfolded protein toxicity, but also other cell types could be affected, suggesting that ALS is a non-cell autonomous disease. So far, whether motoneuron and muscle degeneration involve the same mechanisms is not clear. Our previous data strongly suggest that muscle cells better manage misfolded mutated-SOD1 species than motoneuronal cells due to their higher degradative power and that mutated-SOD1 largely accumulates in spinal cord, but not in muscle of transgenic ALS mice. In the present study we compared the capacity of motoneuron and muscle cells to respond to proteotossic stress (e.g: proteasome and autophagy inhibition). We found that muscle cells activate the autophagy markers LC3 and p62 and the chaperone HSPB8 at higher extent than motoneuron cells. Interestingly, the overexpression in muscle cells of mutated-TDP43 (which does not aggregate) increases the levels of HSPB8 and the knock-down of HSPB8 increases the aggregation of both wild-type and mutated-TDP43, suggesting its primary role in TDP43 turn-over. These data together with the observation that HSPB8 is upregulated in muscles of ALS transgenic mice only at symptomatic stage strongly suggest HSPB8 as a potential modulator of ALS and that its boosting may represent a valid therapeutic approach. GRANTS: Telethon; AriSLA; Fondazione Cariplo; AFM France; Regione Lombardia; UniMI

Role of HSPB8 in a muscular model of amyotrophic lateral sclerosis (ALS) / A. Boncoraglio, V. Crippa, E. Onesto, R. Galbiati, P. Rusmini, E. Giorgetti, R. Cristofani, A. Poletti. ((Intervento presentato al 10. convegno Annual Meeting Interuniversity Institute of Miology tenutosi a Monteriggioni nel 2013.

Role of HSPB8 in a muscular model of amyotrophic lateral sclerosis (ALS)

A. Boncoraglio
Primo
;
V. Crippa
Secondo
;
R. Galbiati;P. Rusmini;E. Giorgetti;R. Cristofani;A. Poletti
Ultimo
2013-10-12

Abstract

The aggregation of misfolded, mutated proteins (Superoxide-Dismutase-1, SOD1; TAR-DNA-binding-protein-43, TDP-43) is a pathological hallmark of familial forms of Amyotrophic Lateral Sclerosis (ALS), suggesting that the protein quality control system (molecular chaperones and the degradative systems ubiquitin-proteasome and autophagy) is saturated or not sufficient to maintain a correct proteostasis. Motoneurons are particularly sensitive to misfolded protein toxicity, but also other cell types could be affected, suggesting that ALS is a non-cell autonomous disease. So far, whether motoneuron and muscle degeneration involve the same mechanisms is not clear. Our previous data strongly suggest that muscle cells better manage misfolded mutated-SOD1 species than motoneuronal cells due to their higher degradative power and that mutated-SOD1 largely accumulates in spinal cord, but not in muscle of transgenic ALS mice. In the present study we compared the capacity of motoneuron and muscle cells to respond to proteotossic stress (e.g: proteasome and autophagy inhibition). We found that muscle cells activate the autophagy markers LC3 and p62 and the chaperone HSPB8 at higher extent than motoneuron cells. Interestingly, the overexpression in muscle cells of mutated-TDP43 (which does not aggregate) increases the levels of HSPB8 and the knock-down of HSPB8 increases the aggregation of both wild-type and mutated-TDP43, suggesting its primary role in TDP43 turn-over. These data together with the observation that HSPB8 is upregulated in muscles of ALS transgenic mice only at symptomatic stage strongly suggest HSPB8 as a potential modulator of ALS and that its boosting may represent a valid therapeutic approach. GRANTS: Telethon; AriSLA; Fondazione Cariplo; AFM France; Regione Lombardia; UniMI
Settore BIO/13 - Biologia Applicata
Role of HSPB8 in a muscular model of amyotrophic lateral sclerosis (ALS) / A. Boncoraglio, V. Crippa, E. Onesto, R. Galbiati, P. Rusmini, E. Giorgetti, R. Cristofani, A. Poletti. ((Intervento presentato al 10. convegno Annual Meeting Interuniversity Institute of Miology tenutosi a Monteriggioni nel 2013.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/237801
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