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RESEARCH PRODUCT
Loss of synaptic zinc transport in progranulin deficient mice may contribute to progranulin-associated psychopathology and chronic pain
Annett Wilken-schmitzStefanie HardtLucie ValekJuliana HeidlerBoris AlbuquerqueMichael K. E. SchäferIrmgard TegederChristine AltmannIlka Wittigsubject
0301 basic medicineNeurotransmitter transportermedicine.medical_specialtyMice03 medical and health sciencesProgranulins0302 clinical medicinePeripheral Nerve InjuriesInternal medicinemental disordersmedicineAnimalsPrefrontal cortexMolecular BiologyGranulinsMice KnockoutIon Transportbusiness.industryChronic painmedicine.diseaseZinc030104 developmental biologyNociceptionEndocrinologyCompulsive behaviorNeuropathic painPeripheral nerve injuryIntercellular Signaling Peptides and ProteinsNeuralgiaMolecular MedicineChronic Painmedicine.symptomCarrier Proteinsbusiness030217 neurology & neurosurgeryFrontotemporal dementiadescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-11-01 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease |