Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two neurodegenerative diseases in which similar pathogenic mechanisms are involved. Both diseases associate to the high propensity of specific misfolded proteins, like TDP-43 or FUS, to mislocalize and aggregate. This is partly due to their intrinsic biophysical properties and partly as a consequence of failure of the neuronal protein quality control (PQC) system. Several familial ALS/FTD cases are linked to an expansion of a repeated G4C2 hexanucleotide sequence present in the C9ORF72 gene. The G4C2, which localizes in an untranslated region of the C9ORF72 transcript, drives an unconventional repeat-associated ATG-independent translation. This leads to the synthesis of five different dipeptide repeat proteins (DPRs), which are not "classical" misfolded proteins, but generate aberrant aggregation-prone unfolded conformations poorly removed by the PQC system. The DPRs accumulate into p62/SQSTM1 and ubiquitin positive inclusions. Here, we analyzed the biochemical behavior of the five DPRs in immortalized motoneurons. Our data suggest that while the DPRs are mainly processed via autophagy, this system is unable to fully clear their aggregated forms, and thus they tend to accumulate in basal conditions. Overexpression of the small heat shock protein B8 (HSPB8), which facilitates the autophagy-mediated disposal of a large variety of classical misfolded aggregation-prone proteins, significantly decreased the accumulation of most DPR insoluble species. Thus, the induction of HSPB8 might represent a valid approach to decrease DPR-mediated toxicity and maintain motoneuron viability.

The small heat shock protein B8 (HSPB8) efficiently removes aggregating species of dipeptides produced in C9ORF72-related neurodegenerative diseases / R. Cristofani, V. Crippa, G. Vezzoli, P. Rusmini, M. Galbiati, M.E. Cicardi, M. Meroni, V. Ferrari, B. Tedesco, M. Piccolella, E. Messi, S. Carra, A. Poletti. - In: CELL STRESS & CHAPERONES. - ISSN 1355-8145. - (2017 Jun 12). [Epub ahead of print] [10.1007/s12192-017-0806-9]

The small heat shock protein B8 (HSPB8) efficiently removes aggregating species of dipeptides produced in C9ORF72-related neurodegenerative diseases

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

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two neurodegenerative diseases in which similar pathogenic mechanisms are involved. Both diseases associate to the high propensity of specific misfolded proteins, like TDP-43 or FUS, to mislocalize and aggregate. This is partly due to their intrinsic biophysical properties and partly as a consequence of failure of the neuronal protein quality control (PQC) system. Several familial ALS/FTD cases are linked to an expansion of a repeated G4C2 hexanucleotide sequence present in the C9ORF72 gene. The G4C2, which localizes in an untranslated region of the C9ORF72 transcript, drives an unconventional repeat-associated ATG-independent translation. This leads to the synthesis of five different dipeptide repeat proteins (DPRs), which are not "classical" misfolded proteins, but generate aberrant aggregation-prone unfolded conformations poorly removed by the PQC system. The DPRs accumulate into p62/SQSTM1 and ubiquitin positive inclusions. Here, we analyzed the biochemical behavior of the five DPRs in immortalized motoneurons. Our data suggest that while the DPRs are mainly processed via autophagy, this system is unable to fully clear their aggregated forms, and thus they tend to accumulate in basal conditions. Overexpression of the small heat shock protein B8 (HSPB8), which facilitates the autophagy-mediated disposal of a large variety of classical misfolded aggregation-prone proteins, significantly decreased the accumulation of most DPR insoluble species. Thus, the induction of HSPB8 might represent a valid approach to decrease DPR-mediated toxicity and maintain motoneuron viability.
HSPB8; motor neuron diseases; protein aggregation; protein clearance; RAN translation
Settore BIO/13 - Biologia Applicata
   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
12-giu-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  
art%3A10.1007%2Fs12192-017-0806-9.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 1.97 MB
Formato Adobe PDF
1.97 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/2434/504712
Citazioni
  • ???jsp.display-item.citation.pmc??? 40
  • Scopus 65
  • ???jsp.display-item.citation.isi??? 61
social impact