Journal
CELL STRESS & CHAPERONES
Volume 23, Issue 1, Pages 1-12Publisher
SPRINGER
DOI: 10.1007/s12192-017-0806-9
Keywords
RAN translation; Protein aggregation; Protein clearance; HSPB8; Motor neuron diseases
Categories
Funding
- Fondazione Telethon, Italy [GGP14039]
- Fondazione Cariplo, Italy [2014-0686]
- Fondazione AriSLA, Italy [ALS_HSPB8, ALS_Granulopathy]
- Association Francaise contre les Myopathies, France (AFM Telethon) [16406]
- Regione Lombardia
- Universita degli Studi di Milano e piano di sviluppo UNIMI-linea B
- Italian Ministry of Health (MinSal) [GR-2011-02347198]
- Fondazione Regionale per la Ricerca Biomedica (FRRB) (TRANS_ALS), Regione Lombardia, Italy
- MIUR Rita Levi Montalcini
- Italian Ministry of University and Research (MIUR), PRIN-Progetti di Ricerca di Interesse Nazionale [2015LFPNMN]
- European Molecular Biology Organization (EMBO) [537-2015]
- European Union [643417, 01ED1601A]
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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.
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