Protein aggregates in motoneurons are a common hallmark of motoneuron diseases (MNDs), including spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS). In MNDs, the protein quality control system prevents protein aggregation. We found that dynein mediated transport is an essential process for misfolded and aggregated protein delivery to degradative sites. Its blockage inhibits macroautophagy. In this condition the co-chaperone BCL2-Associated Athanogene 1 (BAG1) mRNA levels greatly increase to routes misfolded protein to proteasome. Indeed, exogenous BAG1 overexpression reduces misfolded protein accumulation via their proteasome degradation. However, dynein inhibition reduces misfolded insoluble species also when macroautophagy and proteasome are both inhibited. Interestingly, BAG1 can associate HSPA8/HSC70 routing misfolded proteins also to chaperone-mediated autophagy (CMA). After the recognition by HSPA8, proteins are translocated to the lysosomal receptor LAMP2A that allows their insertion into the lumen of competent lysosomes. Dynein inhibition did not modify the mRNA levels of all autophagy markers tested, but significantly increased Lamp2A mRNA and protein levels, but it reduced Lamp1 protein levels suggesting that lysosomal number was reduced. To prove CMA involvement in mifolded protein clearance upon dynein inhibition we used alpha-synuclein (SNCA), a well-established CMA substrate and we found that dynein inhibition increased its clearance. These data show that when macroautophagy is impaired the accumulation of toxic misfolded protein could be prevented by proteasome and CMA degradation. Since CMA is a ubiquitous pathway, it is a conceivable that CMA can be used as a potential pharmacological target to increase the clearance of misfolded proteins.

Chaperone mediated autophagy responds to macroautophagy inhibition in motor neuron diseases / R.M. Cristofani, V. Crippa, M.E. Cicardi, P. Rusmini, M. Meroni, V. Ferrari, B. Tedesco, M. Galbiati, E. Messi, M. Piccolella, G. Sala, C. Ferrarese, A. Poletti. ((Intervento presentato al 18. convegno Congresso Nazionale AIBG tenutosi a Ferrara nel 2018.

Chaperone mediated autophagy responds to macroautophagy inhibition in motor neuron diseases

R.M. Cristofani
Primo
;
V. Crippa;M.E. Cicardi;P. Rusmini;M. Meroni;V. Ferrari;B. Tedesco;M. Galbiati;E. Messi;M. Piccolella;A. Poletti
Ultimo
2018

Abstract

Protein aggregates in motoneurons are a common hallmark of motoneuron diseases (MNDs), including spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS). In MNDs, the protein quality control system prevents protein aggregation. We found that dynein mediated transport is an essential process for misfolded and aggregated protein delivery to degradative sites. Its blockage inhibits macroautophagy. In this condition the co-chaperone BCL2-Associated Athanogene 1 (BAG1) mRNA levels greatly increase to routes misfolded protein to proteasome. Indeed, exogenous BAG1 overexpression reduces misfolded protein accumulation via their proteasome degradation. However, dynein inhibition reduces misfolded insoluble species also when macroautophagy and proteasome are both inhibited. Interestingly, BAG1 can associate HSPA8/HSC70 routing misfolded proteins also to chaperone-mediated autophagy (CMA). After the recognition by HSPA8, proteins are translocated to the lysosomal receptor LAMP2A that allows their insertion into the lumen of competent lysosomes. Dynein inhibition did not modify the mRNA levels of all autophagy markers tested, but significantly increased Lamp2A mRNA and protein levels, but it reduced Lamp1 protein levels suggesting that lysosomal number was reduced. To prove CMA involvement in mifolded protein clearance upon dynein inhibition we used alpha-synuclein (SNCA), a well-established CMA substrate and we found that dynein inhibition increased its clearance. These data show that when macroautophagy is impaired the accumulation of toxic misfolded protein could be prevented by proteasome and CMA degradation. Since CMA is a ubiquitous pathway, it is a conceivable that CMA can be used as a potential pharmacological target to increase the clearance of misfolded proteins.
21-set-2018
Settore BIO/13 - Biologia Applicata
Settore BIO/09 - Fisiologia
Chaperone mediated autophagy responds to macroautophagy inhibition in motor neuron diseases / R.M. Cristofani, V. Crippa, M.E. Cicardi, P. Rusmini, M. Meroni, V. Ferrari, B. Tedesco, M. Galbiati, E. Messi, M. Piccolella, G. Sala, C. Ferrarese, A. Poletti. ((Intervento presentato al 18. convegno Congresso Nazionale AIBG tenutosi a Ferrara nel 2018.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/594772
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