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

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.

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Acknowledgements

This study was supported by the Parkinson Fonds Deutschland, the Hilde-Ulrichs-Stiftung, the Friede-Springer-Stiftung, and the Förderprogramm Forschung und Lehre (FöFoLe) , Ludwig Maximilian University, Munich, Germany (all to T.K.). Günter Höglinger was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198), Deutsche Forschungsgemeinschaft (DFG, HO2402/18-1 MSAomics), the German Federal Ministry of Education and Research (BMBF, 01KU1403A EpiPD; 01EK1605A HitTau), the NOMIS foundation (FTLD project), the Parkinson Fonds Deutschland (Hypothesis-free compound screen, alpha-Synuclein fragments in PD). Jorg Tost was funded by the French National Agency for Reserach (ANR, ANR-13 - EPIG - 0003 - 02, EPIPD, and ANR-18-RAR3-0001-01, MSAomics). Jochen Herms was funded by DZNE and by the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the Munich Cluster for Systems Neurology (SyNergy, EXC 2145 / ID 390857198). We thank the Munich Brain Bank for supplying brain tissue samples. We thank Prof. J. Behrends and Dr. D. Steinbrenner for their technical assistance with patch-clamp recording.

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Tan, Y., Sgobio, C., Arzberger, T. et al. Loss of fragile X mental retardation protein precedes Lewy pathology in Parkinson’s disease. Acta Neuropathol 139, 319–345 (2020). https://doi.org/10.1007/s00401-019-02099-5

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Keywords

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