Antipsychotic drugs counteract autophagy and mitophagy in multiple sclerosis

Selene Ingusci,Saverio Marchi,Silvia Zucchini,Maura Pugliatti,Simone Patergnani,Mariusz R Wieckowski,Mariasole Perrone,Massimo Bonora,Maurizio Previati,Paolo Pinton,Massimiliano Castellazzi,Carlotta Giorgi,Michele Simonato

doi:10.1073/pnas.2020078118

Abstract

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and ultimately neuronal loss. The etiology and physiopathology of MS are still elusive, and no fully effective therapy is yet available. We investigated the role in MS of autophagy (physiologically, a controlled intracellular pathway regulating the degradation of cellular components) and of mitophagy (a specific form of autophagy that removes dysfunctional mitochondria). We found that the levels of autophagy and mitophagy markers are significantly increased in the biofluids of MS patients during the active phase of the disease, indicating activation of these processes. In keeping with this idea, in vitro and in vivo MS models (induced by proinflammatory cytokines, lysolecithin, and cuprizone) are associated with strongly impaired mitochondrial activity, inducing a lactic acid metabolism and prompting an increase in the autophagic flux and in mitophagy. Multiple structurally and mechanistically unrelated inhibitors of autophagy improved myelin production and normalized axonal myelination, and two such inhibitors, the widely used antipsychotic drugs haloperidol and clozapine, also significantly improved cuprizone-induced motor impairment. These data suggest that autophagy has a causal role in MS; its inhibition strongly attenuates behavioral signs in an experimental model of the disease. Therefore, haloperidol and clozapine may represent additional therapeutic tools against MS.

Highlights

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and neuronal loss
By analyzing a new cohort of patients, we found increased levels of autophagy-related 5 (ATG5) and of many other markers of autophagy (namely coiled-coil, moesin-like BCL2-interacting protein, Beclin-1; ATG7; microtubuleassociated proteins 1A/1B light chain 3, LC3; unc-51–like autophagyactivating kinase 1, ULK1; and tryptophan-aspartic acid (WD) repeat domain phosphoinositide–interacting 2 WIPI2) in the cerebrospinal fluid (CSF) and serum of MS patients compared with patients with no inflammatory neurological disease, used as controls
It has been demonstrated that, in the early stage of a demyelinating attack, the expression of nuclear receptor coactivator 4 (NCOA4) and of the transferrin receptor (TFR) increase, whereas they decrease while the demyelination occurs [33], probably due to the execution of the autophagic process. In keeping with these studies, we found that the proinflammatory cytokines TNF-α and IL-1-β cause myelin basic protein (MBP) loss and increase the autophagy flux and activate the ferritinophagic flux, as demonstrated by reduced levels of NCOA4 and TFR (SI Appendix, Fig. S2H), and trigger the release of high-mobility group box 1 (HMGB1) (SI Appendix, Fig. S2I)

Summary

Introduction

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and neuronal loss. Multiple structurally and mechanistically unrelated inhibitors of autophagy improved myelin production and normalized axonal myelination, and two such inhibitors, the widely used antipsychotic drugs haloperidol and clozapine, significantly improved cuprizone-induced motor impairment. These data suggest that autophagy has a causal role in MS; its inhibition strongly attenuates behavioral signs in an experimental model of the disease. The initial phase of MS is characterized by signs of an autoimmune response including disruption of the blood–brain barrier, invasion of the CNS by immune cells, and presence of antibodies against myelin These are believed to play a causative role in the onset of the disease. In Alzheimer’s disease, for example, impairment of the autophagic flux due to reduced vesicle clearance has been associated to accumulation of an aggregated form of hyperphosphorylated tau protein and to Significance

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