Methamphetamine persistently increases alpha-synuclein and suppresses gene promoter methylation within striatal neurons

Francesca Biagioni, Rosangela Ferese, Fiona Limanaqi, Michele Madonna, Paola Lenzi, Stefano Gambardella, Francesco Fornai

Research output: Contribution to journalArticle

Abstract

Methamphetamine (Meth) produces a variety of epigenetic effects in the brain, which are seminal to establish long-lasting alterations in neuronal activity. However, most epigenetic changes were described by measuring the rough amount of either histone acetylation and methylation or direct DNA methylation, without focusing on a specific DNA sequence. This point is key to comprehend Meth-induced phenotypic changes, brain plasticity, addiction and neurodegeneration. In this research paper we analyze the persistence of Meth-induced striatal synucleinopathy at a prolonged time interval of Meth withdrawal. At the same time, Meth-induced alterations, specifically within alpha-synuclein gene (SNCA) or its promoter, were evaluated. We found that exposure to high and/or prolonged doses of Meth, apart from producing nigro-striatal toxicity, determines a long-lasting increase in striatal alpha-synuclein levels. This is consistent along immune-blotting, immune-histochemistry, and electron microscopy. This was neither associated with an increase of SNCA copy number nor with alterations within SNCA sequence. However, we documented persistently demethylation within SNCA promoter, which matches the increase in alpha-synuclein protein. The amount of the native protein, which was measured stoichiometrically within striatal neurons, surpasses the increase reported following SNCA multiplications. Demethylation was remarkable (ten-fold of controls) and steady, even at prolonged time intervals being tested so far (up to 21 days of Meth withdrawal). Similarly alpha-synuclein protein assayed stoichiometrically steadily increased roughly ten-fold of controls. Meth-induced increase of alpha-synuclein was also described within limbic areas. These findings are discussed in the light of Meth-induced epigenetic changes, Meth-induced phenotype alterations, and Meth-induced neurodegeneration.

Original languageEnglish
Pages (from-to)157-175
Number of pages19
JournalBrain Research
Volume1719
DOIs
Publication statusPublished - Sep 15 2019

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Corpus Striatum
alpha-Synuclein
Methamphetamine
Methylation
Neurons
Genes
Epigenomics
Proteins
Brain
DNA Methylation
Acetylation
Histones
Electron Microscopy

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Methamphetamine persistently increases alpha-synuclein and suppresses gene promoter methylation within striatal neurons. / Biagioni, Francesca; Ferese, Rosangela; Limanaqi, Fiona; Madonna, Michele; Lenzi, Paola; Gambardella, Stefano; Fornai, Francesco.

In: Brain Research, Vol. 1719, 15.09.2019, p. 157-175.

Research output: Contribution to journalArticle

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AU - Madonna, Michele

AU - Lenzi, Paola

AU - Gambardella, Stefano

AU - Fornai, Francesco

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