Abstract
ERp57 (also known as grp58 and PDIA3) is a protein disulfide isomerase that catalyzes disulfide bonds formation of glycoproteins as part of the calnexin and calreticulin cycle. ERp57 is markedly upregulated in most common neurodegenerative diseases downstream of the endoplasmic reticulum (ER) stress response. Despite accumulating correlative evidence supporting a neuroprotective role of ERp57, the contribution of this foldase to the physiology of the nervous system remains unknown. Here we developed a transgenic mouse model that overexpresses ERp57 in the nervous system under the control of the prion promoter. We analyzed the susceptibility of ERp57 transgenic mice to undergo neurodegeneration. Unexpectedly, ERp57 overexpression did not affect dopaminergic neuron loss and striatal denervation after injection of a Parkinson's disease-inducing neurotoxin. In sharp contrast, ERp57 transgenic animals presented enhanced locomotor recovery after mechanical injury to the sciatic nerve. These protective effects were associated with enhanced myelin removal, macrophage infiltration and axonal regeneration. Our results suggest that ERp57 specifically contributes to peripheral nerve regeneration, whereas its activity is dispensable for the survival of a specific neuronal population of the central nervous system. These results demonstrate for the first time a functional role of a component of the ER proteostasis network in peripheral nerve regeneration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axons / physiology*
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Cell Survival / drug effects
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Cell Survival / genetics
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Corpus Striatum / metabolism
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Denervation
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Dopaminergic Neurons / drug effects
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Dopaminergic Neurons / metabolism
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Dopaminergic Neurons / pathology
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Female
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Gene Expression
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Humans
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Male
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Mice
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Mice, Transgenic
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Models, Animal
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Motor Activity / genetics
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Nerve Degeneration / genetics
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Nerve Degeneration / pathology
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Nervous System Physiological Phenomena
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Oxidopamine / pharmacology
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Peripheral Nerve Injuries / genetics
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Peripheral Nerve Injuries / physiopathology
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Peripheral Nerve Injuries / rehabilitation
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Protein Disulfide-Isomerases / genetics*
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Protein Disulfide-Isomerases / metabolism*
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Regeneration*
Substances
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Oxidopamine
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Protein Disulfide-Isomerases
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PDIA3 protein, human
Grants and funding
This work was funded by Ring Initiative ACT1109 (FC and CH), FONDEF D11I1007, Millennium Institute No. P09-015-F, the Frick Foundation, FONDECYT no. 1140549, Michael J Fox Foundation for Parkinson Research, the Alzheimer's Association, the Muscular Dystrophy Association, COPEC-UC Foundation, CONICYT grant USA2013-0003, ECOS-CONICYT C13S02, and ALS Therapy Alliance (CH). Millennium Nucleus P-07-011-F, FONDECYT no. 1110987 (FC), FONDECYT no.1150608 (RV). FONDECYT no. 3130351 (DM), FONDECYT no. 3120146 (GM), CONICYT PAI No 82130031. VC, PR and MO are postgraduate fellows supported by a CONICYT fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.