Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ, Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease. Science. 2017 Sep 1;357(6354):891-898. PubMed.

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  1. This work from the Scherzer laboratory is exciting. As an early funder of this work, we are happy to see the publication that summarizes preclinical research combined with a unique epidemiological investigation that supports a novel approach to modulating α-synuclein. Alpha-Synculein is a high priority Parkinson’s target and we are pleased to have another strategy for intervention. As with any therapeutic approach, if β2AR agonists are going to be tested in the clinic, careful consideration to dosing, safety, and pharmacodynamic biomarkers will be essential to design an informative study.

    View all comments by Mark Frasier

  2. The protein α-synuclein is a key component in both familiar and sporadic Parkinson’s disease pathophysiology. Point mutations in the α-synuclein gene (SNCA), and multiplication of wild-type SNCA, cause familiar parkinsonian syndromes with high penetrance. In addition, several studies suggest that the SNCA gene harbors significant risk haplotypes for sporadic PD (Hernandez et al., 2016). Increased SNCA promoter activity as well as SNCA mRNA and α-synuclein protein levels have been implicated in numerous presumed pathological processes (Villar-Piqué et al., 2016). Thus, α-synuclein dyshomeostasis can be considered as the key process upstream of all other pathological alterations, with increased levels of α-synuclein protein being particularly harmful (Luna and Luk, 2015). 

    Given the strong effects of increased α-synuclein protein expression on PD severity observed in patients with multiplications of wild-type SCNA, decreasing α-synuclein (and avoiding concomitant medication, which increases α-synuclein expression) would be a valuable therapeutic approach. Identification of pharmaceuticals already in use, which modulate α-synuclein expression, provides an instant translational benefit to PD patients.

    References:

    Hernandez DG, Reed X, Singleton AB. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J Neurochem. 2016 Oct;139 Suppl 1:59-74. Epub 2016 Apr 18 PubMed.

    Villar-Piqué A, da Fonseca TL, Outeiro TF. Structure, function and toxicity of alpha-synuclein: the Bermuda triangle in synucleinopathies. J Neurochem. 2015 Jul 18; PubMed.

    Luna E, Luk KC. Bent out of shape: α-Synuclein misfolding and the convergence of pathogenic pathways in Parkinson's disease. FEBS Lett. 2015 Dec 21;589(24 Pt A):3749-59. Epub 2015 Oct 23 PubMed.

    View all comments by Ullrich Wuellner

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