Alteration of protein folding and degradation in als: protective role of the small heat shock protein B8

Protein aggregation is a hallmark of both sporadic and familial forms of Amyotrophic Lateral Sclerosis (ALS). Aggregates derive from inefficient removal of misfolded proteins, and contain the disease-associated protein (e.g. mutated SOD1, TDP-43, FUS, UBQLN2) with components of the ubiquitin-proteasome system (UPS) and molecular chaperones (like Heat Shock Proteins, HSPs). This suggests the existence of alterations of the proteotoxicity responsive machinery. This is composed by molecular chaperones, that recognize and bind misfolded proteins, and by autophagy and proteasome. Together they protect motor neurons from aggregate-neurotoxicity. We found that surviving motor neurons in transgenic ALS mice express high levels of the molecular chaperone HSPB8. This protein is also upregulated in spinal cord of ALS patients. HSPB8 is capable to assist the correct folding, preventing proteins aggregation and thus exerting a neuroprotective role in conformational diseases. A peculiarity of HSPB8 is that, besides its chaperone activity, it may also facilitate the autophagic clearance of misfolded proteins, whitout interfering with UPS. In fact, HSPB8 is known to form a complex with BAG3, Hsc70 and CHIP. CHIP is an E3-ubiquitin ligase that ubiquitinates substrates allowing their recognition by p62 and insertion into the autophagosomes for degradation. Indeed, we found that HSPB8 prevents mutant SOD1 and TDP-43 aggregation by increasing their autophagic degradation, suggesting its protective effect in ALS. Thus, pharmacological induction of HSPB8 expression in motoneurons could represent a promising therapeutic approach. GRANTS: Fondazione AriSLA; AFM Telethon Foundation; Regione Lombardia multicentric project