Objective: The degeneration of dopaminergic (DA) substantia nigra pars compacta (SNc) neurons is a pathological hallmark of Parkinson’s disease (PD). Cell death in PD is associated with the gradual emergence of alpha-synuclein-positive (a-syn) neuronal inclusions, termed Lewy bodies. Previous research implicated alterations of neuronal excitability in DA neuron cell death.
Background: Since the Fragile X Mental Retardation Protein (FMRP) has been shown to control a large number of genes related to neuronal excitability and synaptic function, we here investigated the role of FMRP in a-syn-associated pathology.
Method: We combined biochemical, electrophysiological and imaging techniques to examine the effect of a-syn on FMRP in cultured human dopaminergic neurons in vitro and in the mouse brain in vivo. In addition, we investigated the abundance of FMRP in SNc DA neurons of post-mortem human brain tissue from PD patients and from subjects that had incidental Lewy body disease (iLBD), which is assumed to represent pre-clinical PD and where Lewy pathology was still restricted to the dorsal motor nucleus of the vagus nerve (DMV) and the locus coeruleus (LC).
Results: We found FMRP to be decreased in cultured DA neurons and in the mouse brain in response to a-syn overexpression. Likewise, FMRP was lost in SNc DA neurons of PD patients and in neurons from iLBD cases. Similar to Fragile X Syndrome (FXS) neurons, a-syn-overexpressing cells had an increase in membrane N-type calcium channels, enhanced N-type-mediated calcium currents, increased phosphorylation of the protein translation initiation machinery (p-ERK1/2, p-eIF4E, and p-S6) and, as a consequence, an increased overall protein synthesis. The loss of FMRP appeared to have a protective effect in SNc DA neurons because FMRP knockout mice were resistant to the effect of a-syn on striatal dopamine release.
Conclusion: In summary, our results reveal a new and previously unrecognized role of FMRP in PD. Because iLBD cases likewise exhibited a loss of FMRP but had no Lewy bodies in SNc DA neurons, our data thus suggest the loss of FMRP to be an early pathogenic event that precedes Lewy pathology in PD. Our results will support the examination of FMRP-regulated genes in PD onset and progression.
References: n.a.
To cite this abstract in AMA style:
T. Koeglsperger, Y. Tan, C. Sgobio, T. Arzberger, F. Machleid, Q. Tang, E. Findeiss, J. Tost, T. Chakroun, P. Gao, M. Höllerhage, K. Bötzel, J. Herms, G. Höglinger. The Fragile X Mental Retardation Protein is lost prior to the appearance of Lewy pathology in Parkinson’s disease [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/the-fragile-x-mental-retardation-protein-is-lost-prior-to-the-appearance-of-lewy-pathology-in-parkinsons-disease/. Accessed June 15, 2025.« Back to MDS Virtual Congress 2020
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-fragile-x-mental-retardation-protein-is-lost-prior-to-the-appearance-of-lewy-pathology-in-parkinsons-disease/