期刊
MOLECULAR THERAPY
卷 29, 期 10, 页码 3059-3071出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2021.06.005
关键词
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资金
- National Institute of Neurological Dis-orders and Stroke grant [R01 NS100839]
- Sheffield Memorial Grant of the CSRA Parkinson's Disease Support Group
Supplementation with GM1 gangliosides can reduce levels of α-synuclein, enhance expression of tyrosine hydroxylase, and restore functional neurons.
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.
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