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Dopaminergic lesioning impairs adult hippocampal neurogenesis by distinct modification of α-synuclein.
J Neurosci Res. 2016 Jan; 94(1):62-73.JN

Abstract

Nonmotor symptoms of cognitive and affective nature are present in premotor and motor stages of Parkinson's disease (PD). Neurogenesis, the generation of new neurons, persists throughout the mammalian life span in the hippocampal dentate gyrus. Adult hippocampal neurogenesis may be severely affected in the course of PD, accounting for some of the neuropsychiatric symptoms such as depression and cognitive impairment. Two important PD-related pathogenic factors have separately been attributed to contribute to both PD and adult hippocampal neurogenesis: dopamine depletion and accumulation of α-synuclein (α-syn). In the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model, altered neurogenesis has been linked merely to a reduced dopamine level. Here, we seek to determine whether a distinct endogenous α-syn expression pattern is associated, possibly contributing to the hippocampal neurogenic deficit. We observed a persistent reduction of striatal dopamine and a loss of tyrosine hydroxylase-expressing neurons in the substantia nigra pars compacta in contrast to a complete recovery of tyrosine hydroxylase-immunoreactive dopaminergic fibers within the striatum. However, dopamine levels in the hippocampus were significantly decreased. Survival of newly generated neurons was significantly reduced and paralleled by an accumulation of truncated, membrane-associated, insoluble α-syn within the hippocampus. Specifically, the presence of truncated α-syn species was accompanied by increased activity of calpain-1, a calcium-dependent protease. Our results further substantiate the broad effects of dopamine loss in PD-susceptible brain nuclei, gradually involved in the PD course. Our findings also indicate a detrimental synergistic interplay between dopamine depletion and posttranslational modification of α-syn, contributing to impaired hippocampal plasticity in PD.

Authors+Show Affiliations

Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Department of CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany.Department of CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany.Interdisciplinary Center for Clinical Research Junior Research Group III, Nikolaus-Fiebiger-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Department of Psychiatry and Neurosciences, University of California, San Diego, La Jolla, California.Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26451750

Citation

Schlachetzki, Johannes C M., et al. "Dopaminergic Lesioning Impairs Adult Hippocampal Neurogenesis By Distinct Modification of Α-synuclein." Journal of Neuroscience Research, vol. 94, no. 1, 2016, pp. 62-73.
Schlachetzki JC, Grimm T, Schlachetzki Z, et al. Dopaminergic lesioning impairs adult hippocampal neurogenesis by distinct modification of α-synuclein. J Neurosci Res. 2016;94(1):62-73.
Schlachetzki, J. C., Grimm, T., Schlachetzki, Z., Ben Abdallah, N. M., Ettle, B., Vöhringer, P., Ferger, B., Winner, B., Nuber, S., & Winkler, J. (2016). Dopaminergic lesioning impairs adult hippocampal neurogenesis by distinct modification of α-synuclein. Journal of Neuroscience Research, 94(1), 62-73. https://doi.org/10.1002/jnr.23677
Schlachetzki JC, et al. Dopaminergic Lesioning Impairs Adult Hippocampal Neurogenesis By Distinct Modification of Α-synuclein. J Neurosci Res. 2016;94(1):62-73. PubMed PMID: 26451750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dopaminergic lesioning impairs adult hippocampal neurogenesis by distinct modification of α-synuclein. AU - Schlachetzki,Johannes C M, AU - Grimm,Thomas, AU - Schlachetzki,Zinayida, AU - Ben Abdallah,Nada M B, AU - Ettle,Benjamin, AU - Vöhringer,Patrizia, AU - Ferger,Boris, AU - Winner,Beate, AU - Nuber,Silke, AU - Winkler,Jürgen, Y1 - 2015/10/09/ PY - 2015/06/29/received PY - 2015/09/04/revised PY - 2015/09/21/accepted PY - 2015/10/10/entrez PY - 2015/10/10/pubmed PY - 2016/8/6/medline KW - C-terminal-cleaved α-synuclein KW - MPTP KW - calpain-1 SP - 62 EP - 73 JF - Journal of neuroscience research JO - J Neurosci Res VL - 94 IS - 1 N2 - Nonmotor symptoms of cognitive and affective nature are present in premotor and motor stages of Parkinson's disease (PD). Neurogenesis, the generation of new neurons, persists throughout the mammalian life span in the hippocampal dentate gyrus. Adult hippocampal neurogenesis may be severely affected in the course of PD, accounting for some of the neuropsychiatric symptoms such as depression and cognitive impairment. Two important PD-related pathogenic factors have separately been attributed to contribute to both PD and adult hippocampal neurogenesis: dopamine depletion and accumulation of α-synuclein (α-syn). In the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model, altered neurogenesis has been linked merely to a reduced dopamine level. Here, we seek to determine whether a distinct endogenous α-syn expression pattern is associated, possibly contributing to the hippocampal neurogenic deficit. We observed a persistent reduction of striatal dopamine and a loss of tyrosine hydroxylase-expressing neurons in the substantia nigra pars compacta in contrast to a complete recovery of tyrosine hydroxylase-immunoreactive dopaminergic fibers within the striatum. However, dopamine levels in the hippocampus were significantly decreased. Survival of newly generated neurons was significantly reduced and paralleled by an accumulation of truncated, membrane-associated, insoluble α-syn within the hippocampus. Specifically, the presence of truncated α-syn species was accompanied by increased activity of calpain-1, a calcium-dependent protease. Our results further substantiate the broad effects of dopamine loss in PD-susceptible brain nuclei, gradually involved in the PD course. Our findings also indicate a detrimental synergistic interplay between dopamine depletion and posttranslational modification of α-syn, contributing to impaired hippocampal plasticity in PD. SN - 1097-4547 UR - https://www.unboundmedicine.com/medline/citation/26451750/Dopaminergic_lesioning_impairs_adult_hippocampal_neurogenesis_by_distinct_modification_of_α_synuclein_ L2 - https://doi.org/10.1002/jnr.23677 DB - PRIME DP - Unbound Medicine ER -