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Bazov, I., Sarkisyan, D., Kononenko, O., Watanabe, H., Karpyak, V. M., Yakovleva, T. & Bakalkin, G. (2018). Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics. Translational Psychiatry, 8, Article ID 122.
Open this publication in new window or tab >>Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics
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2018 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, article id 122Article in journal (Refereed) Published
Abstract [en]

Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Neurosciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-358683 (URN)10.1038/s41398-017-0075-5 (DOI)000437025300001 ()29925858 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2009-1709Forte, Swedish Research Council for Health, Working Life and Welfare, 259-2012-23Swedish Research Council, K2014-62X-12190-19-5
Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-17Bibliographically approved
Bazov, I., Sarkisyan, D., Kononenko, O., Watanabe, H., Yakovleva, T., Hansson, A. C., . . . Bakalkin, G. (2018). Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.. Molecular Neurobiology, 55(8), 7049-7061
Open this publication in new window or tab >>Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.
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2018 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 8, p. 7049-7061Article in journal (Refereed) Published
Abstract [en]

Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/κ-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2-containing pathways which may lead to the negative affective state in human alcoholics.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Alcohol addiction, Co-expression of gene clusters, D1-pathway, D2-pathway, Dynorphin, Dysphoria, Nucleus accumbens, Post-mortem human brain tissue, Reward system, κ-opioid receptor
National Category
Biochemistry and Molecular Biology Neurology
Identifiers
urn:nbn:se:uu:diva-343195 (URN)10.1007/s12035-017-0844-4 (DOI)000439758300057 ()29383684 (PubMedID)
Funder
Swedish Research Council, K2014-62X-12190-19-5Forte, Swedish Research Council for Health, Working Life and Welfare, 2009-1709 259-2012-23
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-10-17Bibliographically approved
Ruggeri, B., Macare, C., Stopponi, S., Jia, T., Carvalho, F. M., Robert, G., . . . Schumann, G. (2018). Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents. Journal of Child Psychology and Psychiatry and Allied Disciplines, 9(6), 50-658
Open this publication in new window or tab >>Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents
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2018 (English)In: Journal of Child Psychology and Psychiatry and Allied Disciplines, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 9, no 6, p. 50-658Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Nociceptin is a key regulator linking environmental stress and alcohol drinking. In a genome-wide methylation analysis, we recently identified an association of a methylated region in the OPRL1 gene with alcohol-use disorders.

METHODS: Here, we investigate the biological basis of this observation by analysing psychosocial stressors, methylation of the OPRL1 gene, brain response during reward anticipation and alcohol drinking in 660 fourteen-year-old adolescents of the IMAGEN study. We validate our findings in marchigian sardinian (msP) alcohol-preferring rats that are genetically selected for increased alcohol drinking and stress sensitivity.

RESULTS: We found that low methylation levels in intron 1 of OPRL1 are associated with higher psychosocial stress and higher frequency of binge drinking, an effect mediated by OPRL1 methylation. In individuals with low methylation of OPRL1, frequency of binge drinking is associated with stronger BOLD response in the ventral striatum during reward anticipation. In msP rats, we found that stress results in increased alcohol intake and decreased methylation of OPRL1 in the nucleus accumbens.

CONCLUSIONS: Our findings describe an epigenetic mechanism that helps to explain how psychosocial stress influences risky alcohol consumption and reward processing, thus contributing to the elucidation of biological mechanisms underlying risk for substance abuse.

Keywords
OPRL1 methylation, adolescence, binge drinking, nucleus accumbens, stressful life events
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-343194 (URN)10.1111/jcpp.12843 (DOI)000433335100005 ()29197086 (PubMedID)
Funder
EU, European Research Council, LSHM-CT- 2007-037286EU, European Research Council, LSHM-CT- 2007-602450EU, European Research Council, LSHM-CT- 2007-602805EU, European Research Council, LSHM-CT- 2007-603016Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and WelfareSwedish Research Council FormasWellcome trustGerman Research Foundation (DFG), SM 80/7-1German Research Foundation (DFG), SM 80/7-2German Research Foundation (DFG), SFB 940/1NIH (National Institute of Health)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-08-16Bibliographically approved
Sarkisyan, D., Bazov, I., Watanabe, H., Kononenko, O., Syvänen, A.-C., Schumann, G., . . . Bakalkin, G. (2017). Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation [Letter to the editor]. Acta Neuropathologica, 133(3), 485-487
Open this publication in new window or tab >>Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation
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2017 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 133, no 3, p. 485-487Article in journal, Letter (Refereed) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-316837 (URN)10.1007/s00401-017-1675-0 (DOI)000394961100011 ()28097436 (PubMedID)
Note

Shared first authorship for Sarkisyan D., Bazov I.

Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2017-04-28Bibliographically approved
Kononenko, O., Galatenko, V., Andersson, M., Bazov, I., Watanabe, H., Zhou, X., . . . Bakalkin, G. (2017). Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits. The FASEB Journal, 31(5), 1953-1963
Open this publication in new window or tab >>Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits
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2017 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31, no 5, p. 1953-1963Article in journal (Refereed) Published
Abstract [en]

Regulation of the formation and rewiring of neural circuits by neuropeptides may require coordinated production of these signaling molecules and their receptors that may be established at the transcriptional level. Here, we address this hypothesis by comparing absolute expression levels of opioid peptides with their receptors, the largest neuropeptide family, and by characterizing coexpression (transcriptionally coordinated) patterns of these genes. We demonstrated that expression patterns of opioid genes highly correlate within and across functionally and anatomically different areas. Opioid peptide genes, compared with their receptor genes, are transcribed at much greater absolute levels, which suggests formation of a neuropeptide cloud that covers the receptor-expressed circuits. Surprisingly, we found that both expression levels and the proportion of opioid receptors are strongly lateralized in the spinal cord, interregional coexpression patterns are side specific, and intraregional coexpression profiles are affected differently by left-and right-side unilateral body injury. We propose that opioid genes are regulated as interconnected components of the same molecular system distributed between distinct anatomic regions. The striking feature of this system is its asymmetric coexpression patterns, which suggest side-specific regulation of selective neural circuits by opioid neurohormones.

Keywords
neuropeptides, spinal cord, lateralization
National Category
Natural Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-314798 (URN)10.1096/fj.201601039R (DOI)000399195500017 ()28122917 (PubMedID)
Funder
Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and WelfareSwedish Research Council FormasSwedish InstituteThe Swedish Brain Foundation
Note

De 3 första författarna delar förstaförfattarskapet.

Available from: 2017-02-06 Created: 2017-02-06 Last updated: 2017-05-23Bibliographically approved
Sui, P., Watanabe, H., Artemenko, K., Sun, W., Bakalkin, G., Andersson, M. & Bergquist, J. (2017). Neuropeptide imaging in rat spinal cord with MALDI-TOF MS: Method development for the application in pain-related disease studies. European journal of mass spectrometry, 23(3), 105-115
Open this publication in new window or tab >>Neuropeptide imaging in rat spinal cord with MALDI-TOF MS: Method development for the application in pain-related disease studies
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2017 (English)In: European journal of mass spectrometry, ISSN 1469-0667, E-ISSN 1751-6838, Vol. 23, no 3, p. 105-115Article in journal (Refereed) Published
Abstract [en]

Spinal cord as a connection between brain and peripheral nervous system is an essential material for studying neural transmission, especially in pain-related research. This study was the first to investigate pain-related neuropeptide distribution in rat spinal cord using a matrix-assisted laser desorption ionization-time of flight imaging mass spectrometry (MALDI TOF MS) approach. The imaging workflow was evaluated and showed that MALDI TOF MS provides efficient resolution and robustness for neuropeptide imaging in rat spinal cord tissue. The imaging result showed that in naive rat spinal cord the molecular distribution of haeme, phosphatidylcholine, substance P and thymosin beta 4 were well in line with histological features. Three groups of pain-related neuropeptides, which are cleaved from prodynorphin, proenkephalin and protachykinin-1 proteins were detected. All these neuropeptides were found predominantly localized in the dorsal spinal cord and each group had unique distribution pattern. This study set the stage for future MALDI TOF MS application to elucidate signalling mechanism of pain-related diseases in small animal models.

Keywords
Matrix-assisted laser desorption ionization-time of flight imaging mass spectrometry, neuropathic pain, neuropeptide imaging, rat spinal cord
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-330364 (URN)10.1177/1469066717703272 (DOI)000405717700004 ()28657437 (PubMedID)
Funder
Swedish Research Council, 621-2011-4423, 2015-4870
Available from: 2017-09-28 Created: 2017-09-28 Last updated: 2018-01-13Bibliographically approved
Kononenko, O., Bazov, I., Watanabe, H., Gerashchenko, G., Dyachok, O., Verbeek, D. S., . . . Bakalkin, G. (2017). Opioid precursor protein isoform is targeted to the cell nuclei in the human brain. Biochimica et Biophysica Acta, 1861(2), 246-255
Open this publication in new window or tab >>Opioid precursor protein isoform is targeted to the cell nuclei in the human brain
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2017 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1861, no 2, p. 246-255Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Neuropeptide precursors are traditionally viewed as proteins giving rise to small neuropeptide molecules. Prodynorphin (PDYN) is the precursor protein to dynorphins, endogenous ligands for the κ-opioid receptor. Alternative mRNA splicing of neuropeptide genes may regulate cell- and tissue-specific neuropeptide expression and produce novel protein isoforms. We here searched for novel PDYN mRNA and their protein product in the human brain.

METHODS: Novel PDYN transcripts were identified using nested PCR amplification of oligo(dT) selected full-length capped mRNA. Gene expression was analyzed by qRT-PCR, PDYN protein by western blotting and confocal imaging, dynorphin peptides by radioimmunoassay. Neuronal nuclei were isolated using fluorescence-activated nuclei sorting (FANS) from postmortem human striatal tissue. Immunofluorescence staining and confocal microscopy was performed for human caudate nucleus.

RESULTS: Two novel human PDYN mRNA splicing variants were identified. Expression of one of them was confined to the striatum where its levels constituted up to 30% of total PDYN mRNA. This transcript may be translated into ∆SP-PDYN protein lacking 13 N-terminal amino acids, a fragment of signal peptide (SP). ∆SP-PDYN was not processed to mature dynorphins and surprisingly, was targeted to the cell nuclei in a model cellular system. The endogenous PDYN protein was identified in the cell nuclei in human striatum by western blotting of isolated neuronal nuclei, and by confocal imaging.

CONCLUSIONS AND GENERAL SIGNIFICANCE: High levels of alternatively spliced ∆SP-PDYN mRNA and nuclear localization of PDYN protein suggests a nuclear function for this isoform of the opioid peptide precursor in human striatum.

Keywords
Alternative splicing, Human brain, Neuropeptide precursor protein, Nuclear localization, Prodynorphin
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-316836 (URN)10.1016/j.bbagen.2016.11.002 (DOI)000392680200023 ()27838394 (PubMedID)
Funder
Swedish Research Council, K2014-62X-12190-19-5Swedish Research Council Formas, 2009-1709 259-2012-23
Note

Shared first authorship for Kononenko O., Bazov I.

Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2017-11-29
Ahmed, A. S., Ahmed, M., Li, J., Gu, H. F., Bakalkin, G., Stark, A. & Harris, H. E. (2017). Proteasome inhibitor MG132 modulates inflammatory pain by central mechanisms in adjuvant arthritis.. International journal of rheumatic diseases, 20(1), 25-32
Open this publication in new window or tab >>Proteasome inhibitor MG132 modulates inflammatory pain by central mechanisms in adjuvant arthritis.
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2017 (English)In: International journal of rheumatic diseases, ISSN 1756-185X, Vol. 20, no 1, p. 25-32Article in journal (Refereed) Published
Abstract [en]

AIMS: In rheumatoid arthritis (RA), pain and inflammation are initial symptoms followed by various degrees of bone and cartilage destruction. Previously, we have shown that reversible proteasome inhibitor MG132 attenuates pain and joint inflammation in a rat model of adjuvant-arthritis. Our present study aims to study the effects of MG132 on molecular changes in the dorsal root ganglia (DRG) and in the spinal cord (SC) using the same animal model.

METHODS: Arthritis was induced by heat-killed Mycobacterium butyricum in rats. The expression of substance P (SP) was analyzed by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in DRG and in the SC. The nuclear factor-κB (NF-κB) DNA-binding activity in the SC was analyzed by electromobility shift assay.

RESULTS: Arthritic rats treated daily with MG132 demonstrated a marked reduction of SP gene expression in the DRG and number of SP-positive cells was reduced. In the spinal cord of arthritic rats elevated SP messenger RNA levels were normalized and NF-κB-DNA-binding activity was down-regulated in arthritic rats treated with MG132.

CONCLUSION: Our results indicate that proteasome inhibitor MG132 attenuates pain in adjuvant arthritis by targeting the sensory neuropeptide substance P in the peripheral and central nervous systems. These effects may be mediated through the inhibition of NF-κB activation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-257445 (URN)10.1111/1756-185X.12353 (DOI)000401871700002 ()24702728 (PubMedID)
Available from: 2015-07-02 Created: 2015-07-02 Last updated: 2017-06-14Bibliographically approved
Bivehed, E., Strömvall, R., Bergquist, J., Bakalkin, G. & Andersson, M. (2017). Region-specific bioconversion of dynorphin neuropeptide detected by in situ histochemistry and MALDI imaging mass spectrometry. Peptides, 87, 20-27
Open this publication in new window or tab >>Region-specific bioconversion of dynorphin neuropeptide detected by in situ histochemistry and MALDI imaging mass spectrometry
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2017 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 87, p. 20-27Article in journal (Refereed) Published
Abstract [en]

Brain region-specific expression of proteolytic enzymes can control the biological activity of endogenous neuropeptides and has recently been targeted for the development of novel drugs, for neuropathic pain, cancer, and Parkinson's disease. Rapid and sensitive analytical methods to profile modulators of enzymatic activity are important for finding effective inhibitors with high therapeutic value. Combination of in situ enzyme histochemistry with MALDI imaging mass spectrometry allowed developing a highly sensitive method for analysis of brain-area specific neuropeptide conversion of synthetic and endogenous neuropeptides, and for selection of peptidase inhibitors that differentially target conversion enzymes at specific anatomical sites. Conversion and degradation products of Dynorphin B as model neuropeptide and effects of peptidase inhibitors applied to native brain tissue sections were analyzed at different brain locations. Synthetic dynorphin B (2 pmol) was found to be converted to the N-terminal fragments on brain sections whereas fewer C-terminal fragments were detected. N-ethylmaleimide (NEM), a non-selective inhibitor of cysteine peptidases, almost completely blocked the conversion of dynorphin B to dynorphin B(1-6; Leu-Enk-Arg), (1-9), (2-13), and (7-13). Proteinase inhibitor cocktail, and also incubation with acetic acid displayed similar results. Bioconversion of synthetic dynorphin B was region-specific producing dynorphin B(1-7) in the cortex and dynorphin B (2-13) in the striatum. Enzyme inhibitors showed region-and enzyme-specific inhibition of dynorphin bioconversion. Both phosphoramidon (inhibitor of the known dynorphin converting enzyme neprilysin) and opiorphin (inhibitor of neprilysin and aminopeptidase N) blocked cortical bioconversion to dynorphin B(1-7), wheras only opiorphin blocked striatal bioconversion to dynorphin B(2-13). This method may impact the development of novel therapies with aim to strengthen the effects of endogenous neuropeptides under pathological conditions such as chronic pain. Combining histochemistry and MALDI imaging MS is a powerful and sensitive tool for the study of inhibition of enzyme activity directly in native tissue sections. (C) 2016 The Authors. Published by Elsevier Inc.

Keywords
Neuropeptide, Dynorphin, Bioconversion, Enzyme, Enzyme inhibitor, Histochemistry, MALDI imaging mass spectrometry, Mass spectrometry, Parkinson's disease, Neuropathic pain
National Category
Pharmaceutical Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-316129 (URN)10.1016/j.peptides.2016.11.006 (DOI)000392684000003 ()27840228 (PubMedID)
Available from: 2017-03-10 Created: 2017-03-10 Last updated: 2018-01-13Bibliographically approved
Smeets, C. J. L., Zmorzynska, J., Melo, M. N., Stargardt, A., Dooley, C., Bakalkin, G., . . . Verbeek, D. S. (2016). Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA23. Human Molecular Genetics, 25(13), 2728-2737
Open this publication in new window or tab >>Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA23
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2016 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 13, p. 2728-2737Article in journal (Refereed) Published
Abstract [en]

Spinocerebellar ataxia type 23 (SCA23) is caused by missense mutations in prodynorphin, encoding the precursor protein for the opioid neuropeptides alpha-neoendorphin, Dynorphin (Dyn) A and Dyn B, leading to neurotoxic elevated mutant Dyn A levels. Dyn A acts on opioid receptors to reduce pain in the spinal cord, but its cerebellar function remains largely unknown. Increased concentration of or prolonged exposure to Dyn A is neurotoxic and these deleterious effects are very likely caused by an N-methyl-D-aspartate-mediated non-opioidmechanism as Dyn A peptides were shown to bind NMDA receptors and potentiate their glutamate-evoked currents. In the present study, we investigated the cellular mechanisms underlying SCA23-mutant Dyn A neurotoxicity. We show that SCA23 mutations in the Dyn A-coding region disrupted peptide secondary structure leading to a loss of the N-terminal alpha-helix associated with decreased kappa-opioid receptor affinity. Additionally, the altered secondary structure led to increased peptide stability of R6W and R9C Dyn A, as these peptides showed marked degradation resistance, which coincided with decreased peptide solubility. Notably, L5S Dyn A displayed increased degradation and no aggregation. R6W and wt Dyn A peptides were most toxic to primary cerebellar neurons. For R6W Dyn A, this is likely because of a switch from opioid to NMDA-receptor signalling, while for wt Dyn A, this switch was not observed. We propose that the pathology of SCA23 results from converging mechanisms of loss of opioid-mediated neuroprotection and NMDA-mediated excitotoxicity.

National Category
Medicinal Chemistry Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-317067 (URN)10.1093/hmg/ddw130 (DOI)000393064400009 ()27260403 (PubMedID)
Available from: 2017-04-04 Created: 2017-04-04 Last updated: 2018-01-13Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-8074-9833

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