Cystatin C protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity.

S Watanabe,K Yamanaka,T Hayakawa,K Wakasugi

doi:10.1038/cddis.2014.459

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. Cystatin C (CysC), an endogenous cysteine protease inhibitor, is a major protein component of Bunina bodies observed in the spinal motor neurons of sporadic ALS and is decreased in the cerebrospinal fluid of ALS patients. Despite prominent deposition of CysC in ALS, the roles of CysC in the central nervous system remain unknown. Here, we identified the neuroprotective activity of CysC against ALS-linked mutant Cu/Zn-superoxide dismutase (SOD1)-mediated toxicity. We found that exogenously added CysC protected neuronal cells including primary cultured motor neurons. Moreover, the neuroprotective property of CysC was dependent on the coordinated activation of two distinct pathways: autophagy induction through AMPK-mTOR pathway and inhibition of cathepsin B. Furthermore, exogenously added CysC was transduced into the cells and aggregated in the cytosol under oxidative stress conditions, implying a relationship between the neuroprotective activity of CysC and Bunina body formation. These data suggest CysC is an endogenous neuroprotective agent and targeting CysC in motor neurons may provide a novel therapeutic strategy for ALS.

Highlights

Cystatin C (CysC) is an endogenous cysteine protease inhibitor and expressed in various tissues.[8]
We demonstrated the neuroprotective activity of CysC against mutant SOD1-mediated toxicity
As induction of autophagy by CysC protects neurons against various stresses other than SOD1-mediated toxicity[16] and rapamycin protected neurons in mice expressing TAR DNA binding protein 43 (TDP-43), another disease-linked protein accumulated in sporadic Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration,[22] CysC treatment may be useful for SOD1-unrelated ALS as well as the SOD1linked one

Summary

Introduction

Cystatin C (CysC) is an endogenous cysteine protease inhibitor and expressed in various tissues.[8] In the central nervous system, CysC is mainly secreted from the choroid plexus into the cerebrospinal fluid. Especially in the central nervous system, is still uncertain, some studies have revealed that. CysC has a neuroprotective role in neurodegenerative diseases.[10] In a mouse model for Alzheimer’s disease, overexpression of human CysC in the mice reduced deposits of amyloid-β fibrils.[11] CysC has been shown to improve the survival of dopaminergic neurons in a rat model of Parkinson’s disease.[12] In sporadic ALS, CysC is a major component of Bunina bodies, which are ALS-specific inclusion bodies, found in remaining motor neurons,[13] and the levels of CysC are decreased in the cerebrospinal fluid of ALS patients.[14,15]. It was reported that the concentration of CysC in the cerebrospinal fluid is correlated with the survival time of ALS patients,[15] implying a potent neuroprotective property of. Previous reports showed that CysC induces autophagy to protect neuronal cells against various stresses including serum or growth-factor deprivation and oxidative stresses.[10,16]

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Results

Conclusion