Involvement of heterologous ubiquitination including linear ubiquitination in Alzheimer’s disease and amyotrophic lateral sclerosis

Abstract

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. 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. Post-translational modifications, including heterologous ubiquitination, affect proteasomal and autophagic degradation, inflammatory responses, and neurodegeneration. Single nucleotide polymorphisms (SNPs) in SHARPIN and RBCK1 (which encodes HOIL-1L), components of LUBAC, were recently identified as genetic risk factors of 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. Thus, the aberrant LUBAC activity is related to AD. 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. 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.

Linear ubiquitin chains remodel the proteome and influence the levels of hundreds of regulators inDrosophila

“…Ubiquitination is a fundamental post-translational modification that controls the function and levels of target proteins. Recently, linear ubiquitin (UB) chains released from ubiquitinated proteins have emerged as an important form of ubiquitin assembly that may play regulatory roles for many cellular processes, such as immune responses and proteostasis (11,15,17,(20)(21)(22)(23)(24)44). Our previous studies in Drosophila melanogaster demonstrated the versatility of transgene-expressed linear poly-ubiquitin chains that cannot be dismantled into single ubiquitin moieties, which can be conjugated to target proteins or, alternatively, can be themselves ubiquitinated and degraded (20,28,29,45).…”

CRISPR/Cas9-mediated knock-in cells of the late-onset Alzheimer’s disease-risk variant, SHARPIN G186R, reveal reduced NF-κB pathway and accelerated Aβ secretion

“…However, G186R-type SHARPIN appeared to be uniformly distributed in the cytoplasm by immunocytochemistry, whereas it exhibited instability in the soluble fraction of the cell lysate, likely forming aggregates, making extremely difficult of quantitative analysis. Recently, Sato et al [ 36 ] clarified the impact of the G186R mutation from the perspective of structural biology in their review, and they predicted reduced interaction between SHARPIN and HOIL1. They also speculated that glycine at this position in the crystal structure of mouse LUBAC is located in the turn region that connects two helices and that the structure is destabilized by dihedral angle restrictions with residues other than glycine.…”

Fully Human Bifunctional Intrabodies Achieve Graded Reduction of Intracellular Tau and Rescue Survival ofMAPTMutation iPSC-derived Neurons

“…78, 79 During ubiquitin-dependent proteolysis, the C-terminal Gly76 of ubiquitin is reversibly ligated to target proteins or other ubiquitin molecules. 78 Typically, ubiquitin forms polyubiquitin chains through seven internal lysine (K) residues: K6, K11, K27, K29, K33, K48, and K63. Among these, K48-linked ubiquitination is the most common and primarily triggers proteasomal degradation.…”

“…In humans, there are only two ubiquitin-activating enzymes (E1s), ∼40 ubiquitin-conjugating enzymes (E2s), and over 600 ubiquitin-ligase enzymes (E3s) that regulate ubiquitination. 78, 79 During ubiquitin-dependent proteolysis, the C-terminal Gly76 of ubiquitin is reversibly ligated to target proteins or other ubiquitin molecules. 78 Typically, ubiquitin forms polyubiquitin chains through seven internal lysine (K) residues: K6, K11, K27, K29, K33, K48, and K63.…”

“…This is significant because the UPS can be perturbed with neurodegenerative disease. 78, 81, 82 Moreover, approaches that utilize chimeric intrabodies with ubiquitin fusions can inadvertently promote protein aggregation as these fusions can become incorporated into existing protein aggregates. Myeku et al ., observed the co-localization of Ub G76V -eGFP and tau in inclusion bodies within hindbrain neurons in JNPL3:Ub G76V -GFP transgenic mice.…”