Intranasal infusion of GD3 and GM1 gangliosides downregulates alpha-synuclein and controls tyrosine hydroxylase gene in a PD model mouse

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2 Scopus citations

Abstract

Parkinson's disease (PD) is characterized by Lewy bodies (composed predominantly of alpha-synuclein [aSyn]) and loss of pigmented midbrain dopaminergic neurons comprising the nigrostriatal pathway. Most PD patients show significant deficiency of gangliosides, including GM1, in the brain, and GM1 ganglioside appears to keep dopaminergic neurons functioning properly. Thus, supplementation of GM1 could potentially provide some rescuing effects. In this study, we demonstrate that intranasal infusion of GD3 and GM1 gangliosides reduces intracellular aSyn levels. GM1 also significantly enhances expression of tyrosine hydroxylase (TH) in the substantia nigra pars compacta of the A53T aSyn overexpressing mouse, following restored nuclear expression of nuclear receptor related 1 (Nurr1, also known as NR4A2), an essential transcription factor for differentiation, maturation, and maintenance of midbrain dopaminergic neurons. GM1 induces epigenetic activation of the TH gene, including augmentation of acetylated histones and recruitment of Nurr1 to the TH promoter region. Our data indicate that intranasal administration of gangliosides could reduce neurotoxic proteins and restore functional neurons via modulating chromatin status by nuclear gangliosides.

Original languageEnglish (US)
Pages (from-to)3059-3071
Number of pages13
JournalMolecular Therapy
Volume29
Issue number10
DOIs
StatePublished - Oct 6 2021

Keywords

  • alpha-synuclein
  • dopaminergic neuron
  • epigenetic regulation
  • ganglioside therapy
  • GD3 ganglioside
  • GM1 ganglioside
  • hualpha-Syn
  • mitochondrion
  • nurr1
  • Parkinson's disease
  • tyrosine hydroxylase

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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