Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice

Abstract

We showed previously, in a cell model of spinocerebellar ataxia 7, that interferon beta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat multiple sclerosis, might have therapeutic value in spinocerebellar ataxia 7. We now show that interferon beta also induces PML-dependent clearance of ataxin 7 in a preclinical model, SCA7(266Q/5Q) knock-in mice, and improves motor function. Interestingly, the presence of mutant ataxin 7 in the mice induces itself the expression of endogenous interferon beta and its receptor. Immunohistological studies in brains from two patients with spinocerebellar ataxia 7 confirmed that these modifications are also caused by the disease in humans. Interferon beta, administered intraperitoneally three times a week in the knock-in mice, was internalized with its receptor in Purkinje and other cells and translocated to the nucleus. The treatment induced PML protein expression and the formation of PML protein nuclear bodies and decreased mutant ataxin 7 in neuronal intranuclear inclusions, the hallmark of the disease. No reactive gliosis or other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7(266Q/5Q) knock-in mice was significantly improved on two behavioural tests sensitive to cerebellar function: the Locotronic® Test of locomotor function and the Beam Walking Test of balance, motor coordination and fine movements, which are affected in patients with spinocerebellar ataxia 7. In addition to motor dysfunction, SCA7(266Q/5Q) mice present abnormalities in the retina as in patients: ataxin 7-positive neuronal intranuclear inclusions that were reduced by interferon beta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7(266Q/5Q) mice, we showed in primary cell cultures expressing mutant ataxin 7 that interferon beta treatment improves Purkinje cell survival.

ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation

“…41 Moreover, the corresponding neurological disease is partially IFN reversible in mice, strongly suggestive for in vivo activation of this catabolic machinery. 42, 43 Here we demonstrate that Tax is also degraded by this SUMO/PML/RNF4/ proteasome pathway. Tax/PML PLA interactions in HTLV-1-transformed cells are massively increased on proteasome inhibition, strongly suggestive of basal Tax turnover within NBs.…”

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

“…IFNs induce a transient global polyubiquitination 61 , which could result from the hypersumoylation unravelled here. These findings have important therapeutic relevance, as IFNa promotes PML-and SUMO-dependent degradation of toxic proteins in the brain 62,63 or of the HTLV-I leukemia oncoprotein Tax 64 , with unambiguous clinical benefit 62,65,66 . Thus, similar to therapies based on manipulation of ubiquitin-dependent degradation 67,68 , this could pave the way to IFN-triggered, SUMO-based therapies promoting the proteolytic clearance of undesirable proteins 68 .…”

PML nuclear bodies: Assembly and oxidative stress-sensitive sumoylation

“…90 Interferon treatment can induce clearance of ataxin 7 from the brain in a PMLor SUMO-dependent manner, resulting in clinical benefit. [124][125][126] Various other poly-glutamine proteins, such as Huntingtin, were also shown to be cleared in PML NBs. 90 Overall, these findings support a novel and exciting notion whereby utilization of PMLand SUMO-inducing agents (i.e.…”