Ironing out the Alpha Synuclein in Alcohol Use Disorder

Title : Ironing out the Alpha Synuclein in Alcohol Use Disorder

Abstract:

Alpha-synuclein (α-Syn) is a 140-amino acid (aa) protein encoded by the Synuclein alpha gene, SNCA. 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.  Iron deposits are present in the core of Lewy bodies and ferrous iron enhances the aggregation of α-Syn. Both PD and Alcohol Use Disorder (AUD) are associated with liver and brain iron dyshomeostasis. Alpha-Syn has iron import functions with an ability to oxidize the Fe3³⁺ form of iron to Fe2²⁺ to facilitate entry into cells. Increased expression of α-Syn is associated with alcohol use disorder (AUD), and specific genetic variants contribute to the risk for alcoholism, including alcohol craving. We have identified an iron-responsive element (IRE) in the 5' untranslated region (5'UTR) of α-Syn mRNA. Iron response elements are RNA motifs which bind to Iron Regulatory Proteins either to repress the translation  (5’UTR, IREs) or enhance the stability  (3’UTR IREs) of iron regulated genes such that in low iron conditions the iron import, Transferrin receptor mRNA is stabilized (3’UTR IRE) and iron storage protein Ferritin,  containing 5’UTR IRE is repressed. There are at least 17 mRNA variants of α-Syn, the result of alternative splicing of exons 2, 3 and 5,  some which harbor the 5’ UTR IRE and some which do not. The result is the  translation of both full length as well as truncated forms of α-Syn. The presence/absence of IREs in these transcript variants may be able to predict at-risk populations for PD, including secondary Parkinsonism and AUD. Shorter forms of α-Syn with c-terminal truncations, which are more prone to aggregation are associated with both PD and AUD. 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 specific small molecules capable of modulating α-Syn expression that may have the potential to normalize expression in different regions of the alcoholic and PD brain.

Biography:

Dr. Cahill studied Biology at University College Dublin,  Ireland graduating  in 1985 with her Batchelors degree. She received her PhD degree in 1990 at the same institution. After a 3 year postdoctoral fellowship at the Babraham Research Institute,  Cambridge UK, she came to the U.S. where she carried out research at the Dana Farber Cancer Institute and several other Harvard affiliated hospitals including Massachusetts General Hospital.  She is an Assistant Professor of Psychiatry at Massachusetts General Hospital and Co-Directs the Neurochemistry lab with her colleague Dr. Jack Rogers. She has published widely in topics such as  cancer and inflammation, diabetes, neurodegenerative diseases and now alcohol use disorder,  bringing to the field her interdisciplinary background and new perspectives to this research area.