title: FTY720/Fingolimod Reduces Synucleinopathy and Improves Gut Motility in A53T Mice: CONTRIBUTIONS OF PRO-BRAIN-DERIVED NEUROTROPHIC FACTOR (PRO-BDNF) AND MATURE BDNF.
abstract: Patients with Parkinson's disease (PD) often have aggregated α-synuclein (aSyn) in enteric nervous system (ENS) neurons, which may be associated with the development of constipation. This occurs well before the onset of classic PD motor symptoms. We previously found that aging A53T transgenic (Tg) mice closely model PD-like ENS aSyn pathology, making them appropriate for testing potential PD therapies. Here we show that Tg mice overexpressing mutant human aSyn develop ENS pathology by 4 months. We then evaluated the responses of Tg mice and their WT littermates to the Food and Drug Administration-approved drug FTY720 (fingolimod, Gilenya) or vehicle control solution from 5 months of age. Long term oral FTY720 in Tg mice reduced ENS aSyn aggregation and constipation, enhanced gut motility, and increased levels of brain-derived neurotrophic factor (BDNF) but produced no significant change in WT littermates. A role for BDNF was directly assessed in a cohort of young A53T mice given vehicle, FTY720, the Trk-B receptor inhibitor ANA-12, or FTY720 + ANA-12 from 1 to 4 months of age. ANA-12-treated Tg mice developed more gut aSyn aggregation as well as constipation, whereas FTY720-treated Tg mice had reduced aSyn aggregation and less constipation, occurring in part by increasing both pro-BDNF and mature BDNF levels. The data from young and old Tg mice revealed FTY720-associated neuroprotection and reduced aSyn pathology, suggesting that FTY720 may also benefit PD patients and others with synucleinopathy. Another finding was a loss of tyrosine hydroxylase immunoreactivity in gut neurons with aggregated aSyn, comparable with our prior findings in the CNS.
authors.affiliation: From the Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, Texas 79905.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Vidal-Martínez
authors.affiliation: From the Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, Texas 79905.
authors.forename: Javier
authors.initials: J
authors.lastname: Vargas-Medrano
authors.affiliation: From the Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, Texas 79905.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gil-Tommee
authors.affiliation: From the Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, Texas 79905.
authors.forename: David
authors.initials: D
authors.lastname: Medina
authors.affiliation: From the Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, Texas 79905.
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Garza
authors.affiliation: From the Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, Texas 79905.
authors.forename: Barbara
authors.initials: B
authors.lastname: Yang
authors.affiliation: From the Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, Texas 79905.
authors.forename: Ismael
authors.initials: I
authors.lastname: Segura-Ulate
authors.affiliation: From the Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, Texas 79905.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Dominguez
authors.affiliation: From the Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, Texas 79905 ruth.g.perez@ttuhsc.edu.
authors.forename: Ruth G
authors.initials: RG
authors.lastname: Perez
mesh_terms: D000375:Aging / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; C497605:Snca protein, mouse; D051844:alpha-Synuclein; C426674:brain-derived neurotrophic factor precursor; D000068876:Fingolimod Hydrochloride
keywords: Parkinson disease; alpha-synuclein (aSyn); gut; neurodegenerative disease; neuroprotection; pathology; preclinical assessment; synucleinopathy