The role of α-synuclein in the pathophysiology of alcoholism

Abstract

Alcoholism has complex etiology and there is evidence for both genetic and environmental factors in its pathophysiology. Chronic, long-term alcohol abuse and alcohol dependence are associated with neuronal loss with the prefrontal cortex being particularly susceptible to neurotoxic damage. This brain region is involved in the development and persistence of alcohol addiction and neurotoxic damage is likely to exacerbate the reinforcing effects of alcohol and may hinder treatment. Understanding the mechanism of alcohol's neurotoxic effects on the brain and the genetic risk factors associated with alcohol abuse are the focus of current research. Because of its well-established role in neurodegenerative and neuropsychological disorders, and its emerging role in the pathophysiology of addiction, here we review the genetic and epigenetic factors involved in regulating α-synuclein expression and its potential role in the pathophysiology of chronic alcohol abuse. Elucidation of the mechanisms of α-synuclein regulation may prove beneficial in understanding the role of this key synaptic protein in disease and its potential for therapeutic modulation in the treatment of substance use disorders as well as other neurodegenerative diseases.

In vitro aggregation assays for the characterization of α-synuclein prion-like properties

“…The concentration and composition of different alcohols (ethanol, methanol, and propanol) differently affected the fibrillization rate of α-synuclein 73 . Notably, recent studies have established that overexpression of α-synuclein and the consequent higher risk for developing PD is modulated by chronic long-term alcohol exposure 110 , 111 …”

Expresión de alfa sinucleína en sangre y su relación con el estreñimiento crónico en población residente en Bogotá, D.C., con problemas de consumo de alcohol

“…En el presente estudio, el incremento en la concentración de la proteína no fue estadísticamente significativo comparado con los niveles de expresión del ARNm del SNCA por varias razones: en primer lugar, las determinaciones se realizaron en compartimentos diferentes, el ARNm en lisados de células mononucleares de sangre periférica y la proteína en plasma, por lo que no necesariamente tendrían que ser concordantes, como se ha demostrado en diferentes tejidos y regiones cerebrales 4 , 8 , 9 . En segundo lugar, las diferencias podrían deberse a mecanismos de regulación postranscripcionales que impiden la traducción eficaz del ARNm 37 , 38 ; tan es así que los cambios postranscripcionales del ARNm del SNCA están regulados por la presencia de varios microARN, especialmente el mir-7 y el mir-153, que se unen a la región 3 ’ -UTR del SNCA y cuya expresión es inversamente proporcional a la expresión del ARNm y la proteína 39 , 40 .…”

Alpha-Synuclein in Alcohol Use Disorder, Connections with Parkinson’s Disease and Potential Therapeutic Role of 5’ Untranslated Region-Directed Small Molecules

“…One report detected a lower REP1 allele of the shorter type in postmortem prefrontal cortex derived from alcoholic patients, while another study demonstrated increases in the blood of the longer REP1 alleles of α-Syn expression during alcohol withdrawal and linked to craving [ 19 , 20 ]. 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 ]. In fact, the drinking phase of alcoholism was associated with α-Syn promoter hyper-methylation and reduced expression [ 81 ].…”

“…Single-nucleotide polymorphisms (SNPs) in the SNCA gene are associated with alcohol dependence, and some SNPs in the SNCA gene have been associated with alcohol craving [ 18 , 86 ]. First, a haplotype block in the 3′UTR is more abundant in individuals who crave alcohol [ 16 ], and at least 8 SNPs associated with alcoholism were found in intron 4, one of which (rs356168) was also associated with PD [ 80 ] and shown to induce subtle increases in α-Syn mRNA using CRISPR/Cas9 editing in human pluripotent stem cells (HPSCs). Following differentiation into neural cells, it was shown that this non-coding region was likely the binding site of brain-specific transcription factors EMX2 and NKX6-1 [ 87 ].…”