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Acta Neuropathol. 2019 Nov 25. doi: 10.1007/s00401-019-02099-5. [Epub ahead of print]

Loss of fragile X mental retardation protein precedes Lewy pathology in Parkinson's disease.

Author information

1
Department of Translational Neurodegeneration, German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany.
2
Department of Translational Brain Research, German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany.
3
Centre of Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany.
4
Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany.
5
Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie François Jacob, Evry, France.
6
Department of Neurology, Technical University, Munich, Germany.
7
Department of Neurology, Ludwig Maximilian University, Munich, Germany.
8
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
9
Department of Neurology, Hannover Medical School, Hannover, Germany.
10
Department of Translational Neurodegeneration, German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany. thomas.koeglsperger@dzne.de.
11
Department of Neurology, Ludwig Maximilian University, Munich, Germany. thomas.koeglsperger@dzne.de.

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the gradual appearance of α-synuclein (α-syn)-containing neuronal protein aggregates. Although the exact mechanism of α-syn-mediated cell death remains elusive, recent research suggests that α-syn-induced alterations in neuronal excitability contribute to cell death in PD. Because the fragile X mental retardation protein (FMRP) controls the expression and function of numerous neuronal genes related to neuronal excitability and synaptic function, we here investigated the role of FMRP in α-syn-associated pathological changes in cell culture and mouse models of PD as well as in post-mortem human brain tissue from PD patients. We found FMRP to be decreased in cultured DA neurons and in the mouse brain in response to α-syn overexpression. FMRP was, furthermore, lost in the SNc of PD patients and in patients with early stages of incidental Lewy body disease (iLBD). Unlike fragile X syndrome (FXS), FMR1 expression in response to α-syn was regulated by a mechanism involving Protein Kinase C (PKC) and cAMP response element-binding protein (CREB). Reminiscent of FXS neurons, α-syn-overexpressing cells exhibited an increase in membrane N-type calcium channels, increased phosphorylation of ERK1/2, eIF4E and S6, increased overall protein synthesis, and increased expression of Matrix Metalloproteinase 9 (MMP9). FMRP affected neuronal function in a PD animal model, because FMRP-KO mice were resistant to the effect of α-syn on striatal dopamine release. In summary, our results thus reveal a new role of FMRP in PD and support the examination of FMRP-regulated genes in PD disease progression.

KEYWORDS:

Alpha-Synuclein; Fragile X mental retardation protein; Fragile X syndrome; Lewy body disease; N-Type calcium channel; Parkinson’s disease

PMID:
31768670
DOI:
10.1007/s00401-019-02099-5

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