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

• DOI: 10.1007/s12192-017-0806-9
• Publication Date: 2017-06-12T12:29:22Z
• Authors: Riccardo Cristofani; Valeria Crippa; Giulia Vezzoli; Paola Rusmini; Mariarita Galbiati; Maria Elena Cicardi; Marco Meroni; Veronica Ferrari; Barbara Tedesco; Margherita Piccol...; Elio Messi; Serena Carra; Angelo Poletti
• Keywords: C9ORF72

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