Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease targeting preferentially motor neurons. Cyclophilin A (CypA) was identified as a hallmark of disease in mutant SOD1 (mSOD1) animal models of familial ALS (fALS) at a presymptomatic stage, and in sporadic (sALS) patients (Massignan 2007; Nardo 2011). Moreover, CypA was enriched in the spinal cord aggregates of mSOD1 mice and sALS patients (Basso 2009). CypA is an ubiquitous protein with multiple functions relevant to the CNS, where it is abundantly expressed.
Insights into CypA function in ALS were provided via a proteomic analysis of its interacting proteins, that functionally associated CypA with different proteins networks. In particular, it extensively binds proteins regulating RNA metabolism, including several hnRNPs and TDP-43, a major disease protein in ALS. TDP-43 and CypA interact in the nucleus, in an RNA-dependent way. CypA has a key role in the stabilization of TDP-43/hnRNP A2/B1 interaction, and TDP-43-mediated HDAC6 expression regulation, properties impaired in TDP-43 ALS-mutants, possibly because of a loss-of-interaction with CypA. CypA interacts also with mSOD1, suggesting a gain-of-interaction specifically linked to fALS. Mice expressing mSOD1 and lacking CypA show increased levels of insoluble mSOD1 and hyperphosphorylated TDP-43 in the spinal cord at the onset.
This thesis work shows that CypA has a protective role in ALS: as a chaperone (for mSOD1) and in maintenance of multi-protein (TDP-43/hnRNPs) complex stability. Regardless the cause of the disease, mSOD1 or alterations in TDP-43, the interaction with CypA is impaired and it is cosequestered in proteinaceous aggregates, altering its protective activities. The net effect is the formation of pathological inclusions that may lead to a compromised RNA metabolism. CypA being a key interacting partner of both mSOD1 and TDP-43 can represent the "missing link" of these two patho-mechanisms in ALS and an interesting target for therapeutic interventions
