Loss of synaptic zinc transport in progranulin deficient mice may contribute to progranulin-associated psychopathology and chronic pain.

Abstract

Affective and cognitive processing of nociception contributes to the development of chronic pain and vice versa, pain may precipitate psychopathologic symptoms. We hypothesized a higher risk for the latter with immanent neurologic diseases and studied this potential interrelationship in progranulin-deficient mice, which are a model for frontotemporal dementia, a disease dominated by behavioral abnormalities in humans. Young naïve progranulin deficient mice behaved normal in tests of short-term memory, anxiety, depression and nociception, but after peripheral nerve injury, they showed attention-deficit and depression-like behavior, over-activity, loss of shelter-seeking, reduced impulse control and compulsive feeding behavior, which did not occur in equally injured controls. Hence, only the interaction of 'pain x progranulin deficiency' resulted in the complex phenotype at young age, but neither pain nor progranulin deficiency alone. A deep proteome analysis of the prefrontal cortex and olfactory bulb revealed progranulin-dependent alterations of proteins involved in synaptic transport, including neurotransmitter transporters of the solute carrier superfamily. In particular, progranulin deficiency was associated with a deficiency of nuclear and synaptic zinc transporters (ZnT9/Slc30a9; ZnT3/Slc30a3) with low plasma zinc. Dietary zinc supplementation partly normalized the attention deficit of progranulin-deficient mice, which was in part reminiscent of autism-like and compulsive behavior of synaptic zinc transporter Znt3-knockout mice. Hence, the molecular studies point to defective zinc transport possibly contributing to progranulin-deficiency-associated psychopathology. Translated to humans, our data suggest that neuropathic pain may precipitate cognitive and psychopathological symptoms of an inherent, still silent neurodegenerative disease.

• Authors: Stefanie Hardt, Juliana Heidler, Boris Albuquerque, Lucie Valek, Christine Altmann, Annett Wilken-Schmitz, Michael K E Schäfer, Ilka Wittig, Irmgard Tegeder
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1863 Issue 11 Pg. 2727-2745 (11 2017) ISSN: 0925-4439 [Print] Netherlands
• PMID: 28720486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017. Published by Elsevier B.V.

Chemical References

• Carrier Proteins
• Granulins
• Grn protein, mouse
• Intercellular Signaling Peptides and Proteins
• Progranulins
• zinc-binding protein
• Zinc

Topics

• Animals
• Carrier Proteins (genetics, metabolism)
• Chronic Pain (genetics, metabolism, physiopathology, psychology)
• Granulins
• Intercellular Signaling Peptides and Proteins (deficiency)
• Ion Transport
• Mice
• Mice, Knockout
• Neuralgia (genetics, metabolism, physiopathology, psychology)
• Peripheral Nerve Injuries (genetics, metabolism, physiopathology, psychology)
• Progranulins
• Zinc (metabolism)