School of Pharmacy and Pharmacology, Griffith University, Gold Coast, QLD 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia; Quality Use of Medicines Network, Griffith University, Gold Coast, QLD 4222, Australia.
Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia.
Bioorg Chem. 2020 Jan;94:103389. doi: 10.1016/j.bioorg.2019.103389. Epub 2019 Nov 9.
Numerous post-translational modifications (PTMs) of the Parkinson's disease (PD) associated α-synuclein (α-syn) protein have been recognised to play critical roles in disease aetiology. Indeed, dysregulated phosphorylation and proteolysis are thought to modulate α-syn aggregation and disease progression. Among the PTMs, enzymatic glycosylation with N-acetylglucosamine (GlcNAc) onto the protein's hydroxylated amino acid residues is reported to deliver protective effects against its pathogenic processing. This modification has been reported to alter its pathogenic self-assembly. As such, manipulation of the protein's O-GlcNAcylation status has been proposed to offer a PD therapeutic route. However, targeting upstream cellular processes can lead to mechanism-based toxicity as the enzymes governing O-GlcNAc cycling modify thousands of acceptor substrates. Small glycopeptides that couple the protective effects of O-GlcNAc with the selectivity of recognition sequences may prove useful tools to modulate protein aggregation. Here we discuss efforts to probe the effects of various O-GlcNAc modified peptides on wild-type α-synuclein aggregation.
帕金森病（PD）相关的α-突触核蛋白（α-syn）的许多翻译后修饰（PTMs）已被认为在疾病发病机制中起关键作用。事实上，失调的磷酸化和蛋白水解被认为调节α-syn 的聚集和疾病进展。在这些 PTM 中，报道称将 N-乙酰葡萄糖胺（GlcNAc）酶促糖基化到蛋白质的羟基化氨基酸残基上，可提供针对其致病加工的保护作用。据报道，这种修饰改变了其致病的自身组装。因此，已经提出操纵蛋白质的 O-GlcNAc 化状态可以提供 PD 治疗途径。然而，靶向上游细胞过程可能导致基于机制的毒性，因为控制 O-GlcNAc 循环的酶修饰了数千个接受底物。与 O-GlcNAc 的保护作用和识别序列的选择性相结合的小糖肽可能被证明是调节蛋白质聚集的有用工具。在这里，我们讨论了探测各种 O-GlcNAc 修饰肽对野生型 α-突触核蛋白聚集的影响的努力。
