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

Tan, Yi; Sgobio, Carmelo; Arzberger, Thomas; Machleid, Felix; Tang, Qilin; Findeis, Elisabeth; Tost, Jorg; Chakroun, Tasnim; Gao, Pan; Höllerhage, Mathias; Bötzel, Kai; Herms, Jochen; Höglinger, Günter und Köglsperger, Thomas (2020): Loss of fragile X mental retardation protein precedes Lewy pathology in Parkinson's disease. In: Acta Neuropathologica, Bd. 139, Nr. 2: S. 319-345

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 alpha-synuclein (alpha-syn)-containing neuronal protein aggregates. Although the exact mechanism of alpha-syn-mediated cell death remains elusive, recent research suggests that alpha-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 alpha-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 alpha-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 alpha-syn was regulated by a mechanism involving Protein Kinase C (PKC) and cAMP response element-binding protein (CREB). Reminiscent of FXS neurons, alpha-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 alpha-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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0001-6322
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198