Protein ubiquitination is one of the major PTMs. 2 Ubiquitin code 2.1 Ubiquitin code and complex ubiquitination We will therefore focus our discussion on newly developed compounds, such as proteolysis targeting chimeras (PROTACs) and inhibitors for ubiquitin ligases (E3s), which are expected to be potential therapeutic tools to suppress proteinopathies in AD and ALS. The ubiquitin system is attractive as a therapeutic target for neurodegenerative diseases. In this review, we focus on the contributions of heterologous ubiquitinations, including the N-terminal Met1 (M1)-linked linear ubiquitination in AD and ALS, and discuss the effects of SNPs on the structure and activity of SHARPIN, which may explain how these SNPs contribute to AD. Ubiquitin, a 76-residue globular protein, regulates not only proteasomal degradation but also various functions by generating multiple ubiquitin chain linkages. The PTMs also affect the resistance of aggregate proteins toward protein degradation by the ubiquitin-proteasome and/or autophagy-lysosome systems, chronic neuroinflammation, neuronal cell death, and neurodegeneration. Various post-translational modifications (PTMs), such as phosphorylation, ubiquitination, oxidation, acetylation, SUMOylation, and polyADP-ribosylation (PARylation), regulate the protein homeostasis (proteostasis) of these aggregating proteins. The aggregated proteins then exhibit proteotoxicity, called proteinopathy, and a microtubule-associated protein, tau-induced pathology, is specifically referred to as tauopathy ( Dugger and Dickson 2017). These proteins generally include a low-complexity domain that induces misfolding, oligomerization, liquid-liquid phase separation (LLPS), and aggregation. Importantly, each neurodegenerative disease has typical aggregating proteins, such as amyloid β (Aβ) in AD, tau in AD and FTD, α-synuclein in PD, TAR DNA-binding protein 43 (TDP-43) in ALS and FTD, and mutant huntingtin in HD ( Winklhofer et al., 2008). Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington’s disease (HD), and prion diseases, are fatal diseases caused by the progressive loss of structure and function of neurons in the central or peripheral nervous system, and accompanied by protein aggregation and ubiquitin-positive inclusion body formation ( Dugger and Dickson 2017 Boland et al., 2018). Therefore, the development of therapeutic approaches that target ubiquitination, such as proteolysis-targeting chimeras (PROTACs) and inhibitors of ubiquitin ligases, including LUBAC, is expected to be an additional effective strategy to treat neurodegenerative diseases. Protein ubiquitination and ubiquitin-binding proteins, such as ubiquilin 2 and NEMO, facilitate liquid-liquid phase separation (LLPS), and linear ubiquitination seems to promote efficient LLPS. Thus, the aberrant LUBAC activity is related to AD. A structural biological simulation suggested that most of the SHARPIN SNPs that cause an amino acid replacement affect the structure and function of SHARPIN. Single nucleotide polymorphisms (SNPs) in SHARPIN and RBCK1 (which encodes HOIL-1L), components of LUBAC, were recently identified as genetic risk factors of AD. Post-translational modifications, including heterologous ubiquitination, affect proteasomal and autophagic degradation, inflammatory responses, and neurodegeneration. Along with the seven types of Lys-linked ubiquitin chains, the linear ubiquitin chain assembly complex (LUBAC)-mediated Met1-linked linear ubiquitin chain, which activates the canonical NF-κB pathway, is also involved in cytoplasmic inclusions of tau in AD and TAR DNA-binding protein 43 in ALS. In neurodegenerative diseases such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), the progressive accumulation of ubiquitin-positive cytoplasmic inclusions leads to proteinopathy and neurodegeneration. 5Department of Neurology, Wakayama Medical University, Wakayama, Japan.4Department of Molecular and Genetic Medicine, Kawasaki Medical School, Kurashiki, Japan. 3Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.2Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori, Japan.1Center for Research on Green Sustainable Chemistry, Graduate School of Engineering, Tottori University, Tottori, Japan.Yusuke Sato 1,2 Seigo Terawaki 3,4 Daisuke Oikawa 3 Kouhei Shimizu 3 Yoshinori Okina 3 Hidefumi Ito 5 Fuminori Tokunaga 3*
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