The brain-expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been implicated in numerous neurodegenerative diseases including ALS/FTD. UBQLN2 typically resides in the cytoplasm but in disease can translocate to the nucleus, as in Huntington's disease where it promotes the clearance of mutant Huntingtin.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
October 2018
UBQLN2 is one of a family of proteins implicated in ubiquitin-dependent protein quality control and integrally tied to human neurodegenerative disease. Whereas wild-type UBQLN2 accumulates in intraneuronal deposits in several common age-related neurodegenerative diseases, mutations in the gene encoding this protein result in X-linked amyotrophic lateral sclerosis/frontotemporal dementia associated with TDP43 accumulation. Using in vitro protein analysis, longitudinal fluorescence imaging and cellular, neuronal, and transgenic mouse models, we establish that UBQLN2 is intrinsically prone to self-assemble into higher-order complexes, including liquid-like droplets and amyloid aggregates.
View Article and Find Full Text PDFFibrillar aggregates of human islet amyloid polypeptide, hIAPP, a pathological feature seen in some diabetes patients, are a likely causative agent for pancreatic beta-cell toxicity, leading to a transition from a state of insulin resistance to type II diabetes through the loss of insulin producing beta-cells by hIAPP induced toxicity. Because of the probable link between hIAPP and the development of type II diabetes, there has been strong interest in developing reagents to study the aggregation of hIAPP and possible therapeutics to block its toxic effects. Natural products are a class of compounds with interesting pharmacological properties against amyloids which have made them interesting targets to study hIAPP.
View Article and Find Full Text PDFThe deposition of aggregates of human islet amyloid polypeptide (hIAPP) has been correlated with the death of β-cells in type II diabetes mellitus. The actual molecular mechanism of cell death remains largely unknown; however, it has been postulated that the process of aggregation from monomeric hIAPP is closely involved. A possible cause of cellular toxicity may be through the disruption of structural integrity of the cell membrane by IAPP.
View Article and Find Full Text PDFMolecular self-assembly, a phenomenon widely observed in nature, has been exploited through organic molecules, proteins, DNA, and peptides to study complex biological systems. These self-assembly systems may also be used in understanding the molecular and structural biology which can inspire the design and synthesis of increasingly complex biomaterials. Specifically, use of these building blocks to investigate protein folding and misfolding has been of particular value since it can provide tremendous insights into peptide aggregation related to a variety of protein misfolding diseases, or amyloid diseases (e.
View Article and Find Full Text PDFHistone deacetylase 8 (HDAC8) was originally classified as a Zn(II)-dependent deacetylase on the basis of Zn(II)-dependent HDAC8 activity in vitro and illumination of a Zn(II) bound to the active site. However, in vitro measurements demonstrated that HDAC8 has higher activity with a bound Fe(II) than Zn(II), although Fe(II)-HDAC8 rapidly loses activity under aerobic conditions. These data suggest that in the cell HDAC8 could be activated by either Zn(II) or Fe(II).
View Article and Find Full Text PDFThe deposition of aggregates of human islet amyloid peptide (hIAPP) has been correlated with the death of insulin-producing beta (β) cells in type II diabetes mellitus. The actual molecular mechanism of cell death remains unknown; however, it has been postulated that the process of aggregation and amyloid fibril growth from monomeric hIAPP is closely involved. Intermediate IAPP aggregates are highly toxic to islet cells, but lack of structural knowledge of these oligomers and complications in applying biophysical techniques to their study have been the main obstacles in designing structure-based therapeutics.
View Article and Find Full Text PDFA diphenylpropynone derivative, DPP2, has been recently demonstrated to target metal-associated amyloid-β (metal-Aβ) species implicated in Alzheimer's disease (AD). DPP2 was shown to interact with metal-Aβ species and subsequently control Aβ aggregation (reactivity) in vitro; however, its cytotoxicity has limited further biological applications. In order to improve reactivity toward Aβ species and lower cytotoxicity, along with gaining an understanding of a structure-reactivity-cytotoxicity relationship, we designed, prepared, and characterized a series of small molecules (C1/C2, P1/P2, and PA1/PA2) as structurally modified DPP2 analogues.
View Article and Find Full Text PDFIn Alzheimer's disease (AD), metal-associated amyloid-β (metal-Aβ) species have been suggested to be involved in neurotoxicity; however, their role in disease development is still unclear. To elucidate this aspect, chemical reagents have been developed as valuable tools for targeting metal-Aβ species, modulating the interaction between the metal and Aβ, and subsequently altering metal-Aβ reactivity. Herein, we report the design, preparation, characterization, and reactivity of two diphenylpropynone derivatives (DPP1 and DPP2) composed of structural moieties for metal chelation and Aβ interaction (bifunctionality).
View Article and Find Full Text PDFHighly concentrated metals such as Cu, Zn, and Fe are found in amyloid-β (Aβ) plaques within the brain of Alzheimer's disease (AD). In vitro and in vivo studies have suggested that metal binding to Aβ could facilitate Aβ aggregation and generate reactive oxygen species (ROS), which could contribute to the neuropathogenesis of AD. The connection between metal-Aβ interaction/reactivity and AD development, however, has not been clearly revealed owing to the complexity of the disease.
View Article and Find Full Text PDF