FTY720 Improves Behavior, Increases Brain Derived Neurotrophic Factor Levels and Reduces α-Synuclein Pathology in Parkinsonian GM2+/- Mice

Neuroscience. 2019 Jul 15:411:1-10. doi: 10.1016/j.neuroscience.2019.05.029. Epub 2019 May 23.

Abstract

Parkinson's disease (PD) is a progressive aging disorder that affects millions worldwide, thus, disease-modifying-therapies are urgently needed. PD pathology includes α-synuclein (aSyn) accumulation as synucleinopathy. Loss of GM1 gangliosides occurs in PD brain, which is modeled in GM2 synthase transgenic mice. GM2+/- mice have low, not absent GM1 and develop age-onset motor deficits, making them an excellent PD drug testing model. FTY720 (fingolimod) reduces synucleinopathy in A53T aSyn mice and motor dysfunction in 6-OHDA and rotenone PD models, but no one has tested FTY720 in mice that develop age-onset PD-like motor problems. We confirmed that GM2+/-mice had equivalent rotarod, hindlimb reflexes, and adhesive removal functions at 9 mo. From 11 mo, GM2+/- mice received oral FTY720 or vehicle 3x/week to 16 mo. As bladder problems occur in PD, we also assessed GM2+/- bladder function. This allowed us to demonstrate improved motor and bladder function in GM2+/- mice treated with FTY720. By immunoblot, FTY720 reduced levels of proNGF, a biomarker of bladder dysfunction. In humans with PD, arm swing becomes abnormal, and brachial plexus modulates arm swing. Ultrastructure of brachial plexus in wild type and GM2 transgenic mice confirmed abnormal myelination and axons in GM2 transgenics. FTY720 treated GM2+/- brachial plexus sustained myelin associated protein levels and reduced aggregated aSyn and PSer129 aSyn levels. FTY720 increases brain derived neurotrophic factor (BDNF) and we noted increased BDNF in GM2+/- brachial plexus and cerebellum, which contribute to rotarod performance. These findings provide further support for testing low dose FTY720 in patients with PD.

Keywords: brachial plexus synucleinopathy; improved bladder function; low dose drug; motor improvement; myelination biomarker increases; neuroprotection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Brain / drug effects*
  • Brain / metabolism
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Fingolimod Hydrochloride / pharmacology*
  • Fingolimod Hydrochloride / therapeutic use
  • Mice
  • Mice, Transgenic
  • Motor Skills / drug effects
  • N-Acetylgalactosaminyltransferases / genetics
  • N-Acetylgalactosaminyltransferases / metabolism
  • Parkinson Disease, Secondary / drug therapy*
  • Parkinson Disease, Secondary / metabolism
  • Rotarod Performance Test
  • Sphingosine 1 Phosphate Receptor Modulators / pharmacology*
  • Sphingosine 1 Phosphate Receptor Modulators / therapeutic use
  • alpha-Synuclein / metabolism*

Substances

  • Brain-Derived Neurotrophic Factor
  • Sphingosine 1 Phosphate Receptor Modulators
  • alpha-Synuclein
  • N-Acetylgalactosaminyltransferases
  • (N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase
  • Fingolimod Hydrochloride