Motoneuron diseases, like spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS), are associated with proteins that because of gene mutation or peculiar structures, acquire aberrant (misfolded) conformations toxic to cells. To prevent misfolded protein toxicity, cells activate a protein quality control (PQC) system composed of chaperones and degradative pathways (proteasome and autophagy). Inefficient activation of the PQC system results in misfolded protein accumulation that ultimately leads to neuronal cell death, while efficient macroautophagy/autophagy-mediated degradation of aggregating proteins is beneficial. The latter relies on an active retrograde transport, mediated by dynein and specific chaperones, such as the HSPB8-BAG3-HSPA8 complex. Here, using cellular models expressing aggregate-prone proteins involved in SBMA and ALS, we demonstrate that inhibition of dynein-mediated retrograde transport, which impairs the targeting to autophagy of misfolded species, does not increase their aggregation. Rather, dynein inhibition correlates with a reduced accumulation and an increased clearance of mutant ARpolyQ, SOD1, truncated TARDBP/TDP-43 and expanded polyGP C9ORF72 products. The enhanced misfolded proteins clearance is mediated by the proteasome, rather than by autophagy and correlates with the upregulation of the HSPA8 cochaperone BAG1. In line, overexpression of BAG1 increases the proteasome-mediated clearance of these misfolded proteins. Our data suggest that when the misfolded proteins cannot be efficiently transported towards the perinuclear region of the cells, where they are either degraded by autophagy or stored into the aggresome, the cells activate a compensatory mechanism that relies on the induction of BAG1 to target the HSPA8-bound cargo to the proteasome in a dynein-independent manner.

Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases / R. Cristofani, V. Crippa, P. Rusmini, M.E. Cicardi, M. Meroni, N.V. Licata, G. Sala, E. Giorgetti, C. Grunseich, M. Galbiati, M. Piccolella, E. Messi, C. Ferrarese, S. Carra, A. Poletti. - In: AUTOPHAGY. - ISSN 1554-8627. - (2017). [Epub ahead of print] [10.1080/15548627.2017.1308985]

Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases

R. Cristofani
Primo
;
V. Crippa
Secondo
;
P. Rusmini;M.E. Cicardi;M. Meroni;E. Giorgetti;M. Galbiati;M. Piccolella;E. Messi;A. Poletti
Ultimo
2017

Abstract

Motoneuron diseases, like spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS), are associated with proteins that because of gene mutation or peculiar structures, acquire aberrant (misfolded) conformations toxic to cells. To prevent misfolded protein toxicity, cells activate a protein quality control (PQC) system composed of chaperones and degradative pathways (proteasome and autophagy). Inefficient activation of the PQC system results in misfolded protein accumulation that ultimately leads to neuronal cell death, while efficient macroautophagy/autophagy-mediated degradation of aggregating proteins is beneficial. The latter relies on an active retrograde transport, mediated by dynein and specific chaperones, such as the HSPB8-BAG3-HSPA8 complex. Here, using cellular models expressing aggregate-prone proteins involved in SBMA and ALS, we demonstrate that inhibition of dynein-mediated retrograde transport, which impairs the targeting to autophagy of misfolded species, does not increase their aggregation. Rather, dynein inhibition correlates with a reduced accumulation and an increased clearance of mutant ARpolyQ, SOD1, truncated TARDBP/TDP-43 and expanded polyGP C9ORF72 products. The enhanced misfolded proteins clearance is mediated by the proteasome, rather than by autophagy and correlates with the upregulation of the HSPA8 cochaperone BAG1. In line, overexpression of BAG1 increases the proteasome-mediated clearance of these misfolded proteins. Our data suggest that when the misfolded proteins cannot be efficiently transported towards the perinuclear region of the cells, where they are either degraded by autophagy or stored into the aggresome, the cells activate a compensatory mechanism that relies on the induction of BAG1 to target the HSPA8-bound cargo to the proteasome in a dynein-independent manner.
Aggregation; BAG1; BAG3; HSPB8; amyotrophic lateral sclerosis; autophagy; misfolded protein; proteasome; protein quality control
Settore BIO/13 - Biologia Applicata
Settore BIO/09 - Fisiologia
   RAN translation of normal and expanded nucleotide repeat containing transcripts to neurotoxic polypetides in neurodegenerative diseases
   No RAn for old man
   FONDAZIONE CARIPLO
   2014-0686

   Motor neuron degeneration in Spinal and Bulbar Muscular Atrophy: molecular approaches to counteract mutant androgen receptor neurotoxicity
   FONDAZIONE TELETHON ETS
   GGP14039

   Upregulation of HSPB8 as potential therapeutic approach in familial and sporadic ALS
   ALS_HSPB8
   FONDAZIONE ITALIANA DI RICERCA PER LA SLA - SCLEROSI LATERALE AMIOTROFICA - ARISLA
   ALS_HSPB8

   Selective autophagic response to proteotoxicity in motorneurons and muscle of motor neuron diseases
   AFM-TELETHON - ASS. FRANCAISE CONTRE LES MYOPATHIES
   16406-AFMTelethon

   From RNA to Protein toxicity in motorneuron diseases
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   2015LFPNMN_006

   From RNA to Protein toxicity in motorneuron diseases
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   2015LFPNMN_001
2017
12-apr-2017
Centro Interdipartimentale di Eccellenza per le Malattie Neurodegenerative CEND
Centro Interuniversitario di Ricerca sulle Basi Molecolari delle Malattie Neurodegenerative
Article (author)
File in questo prodotto:
File Dimensione Formato  
5772_7_merged_1488299243.pdf

accesso aperto

Tipologia: Pre-print (manoscritto inviato all'editore)
Dimensione 15.85 MB
Formato Adobe PDF
15.85 MB Adobe PDF Visualizza/Apri
Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 2.47 MB
Formato Adobe PDF
2.47 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/491746
Citazioni
  • ???jsp.display-item.citation.pmc??? 44
  • Scopus 61
  • ???jsp.display-item.citation.isi??? 54
social impact