Abstract
Alpha-synuclein (α-Syn) is a 140-amino acid (aa) protein encoded by the Synuclein alpha SNCA gene. It is the synaptic protein associated with Parkinson’s disease (PD) and is the most highly expressed protein in the Lewy bodies associated with PD and other alpha synucleopathies, including Lewy body dementia (LBD) and multiple system atrophy (MSA). Iron deposits are present in the core of Lewy bodies, and there are reports suggesting that divalent metal ions including Cu2+ and Fe2+ enhance the aggregation of α-Syn. Differential expression of α-Syn is associated with alcohol use disorder (AUD), and specific genetic variants contribute to the risk for alcoholism, including alcohol craving. Spliced variants of α-Syn, leading to the expression of several shorter forms which are more prone to aggregation, are associated with both PD and AUD, and common transcript variants may be able to predict at-risk populations for some movement disorders or subtypes of PD, including secondary Parkinsonism. Both PD and AUD are associated with liver and brain iron dyshomeostasis. Research over the past decade has shown that α-Syn has iron import functions with an ability to oxidize the Fe3+ form of iron to Fe2+ to facilitate its entry into cells. Our prior research has identified an iron-responsive element (IRE) in the 5’ untranslated region (5’UTR) of α-Syn mRNA, and we have used the α-Syn 5’UTR to screen for small molecules that modulate its expression in the H4 neuronal cell line. These screens have led us to identify several interesting small molecules capable of both decreasing and increasing α-Syn expression and that may have the potential, together with the recently described mesenchymal stem cell therapies, to normalize α-Syn expression in different regions of the alcoholic and PD brain.
Highlights
Alpha-synuclein (α-Syn) was first discovered as a neuron-specific protein of 143 amino acids in purified cholinergic synaptic vesicles from the electric ray, Torpedo californica
This study demonstrated that longer alleles of REP1 led to a higher expression of α-Syn, which is associated with alcohol dependence, while the shorter alleles correlated with reduced expression of α-Syn in the dorsolateral prefrontal cortex of long-term alcoholics [30,80]
Both βand γ-Syn show a high degree of homology to α-Syn at the protein sequence level, they do not contain iron-responsive element (IRE)-like sequences within their respective mRNAs and do not prominently deposit with α-Syn in brain lesions, making the IRE on α-Syn a highly unique sequence and excellent therapeutic target
Summary
Alpha-synuclein (α-Syn) was first discovered as a neuron-specific protein of 143 amino acids (aas) in purified cholinergic synaptic vesicles from the electric ray, Torpedo californica. Α-Syn is downregulated in expression in the frontal cortex and caudate–putamen of inbred alcohol preferring rats [31], as well as in the brain (amygdala) and blood of the stress reactive DBP (D-Box binding protein) animal model of alcoholism prior to exposure to any alcohol. Degradation or specific proteolysis of α-Syn to shorter more aggregation-prone species may help explain the discrepant results, and the discovery of multiple α-Syn mRNA species that are likely to be prone to differential translational regulation likely leads to expression of specific isoforms in different brain areas in response to alcohol with varying abilities to modulate DA neurotransmission [18,19]. The link between α-Syn protein and mRNA expression in secondary parkinsonism associated with alcohol abuse has yet to be explored
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