Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease (AD)1. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge2. Here, we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase (HDAC) 2, which is increased by AD-related neurotoxic insults in vitro, in two mouse models of neurodegeneration, and in AD patients. HDAC2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the buildup of HDAC2 by shRNA-mediated knockdown unlocks the repression of these genes, re-instates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of HDAC2-selective inhibitors, and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.
SUMMARY Defects in DNA repair have been extensively linked to neurodegenerative diseases, but the exact mechanisms remain poorly understood. Here, we report that FUS, a RNA/DNA binding protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), plays a pivotal role in DNA damage response (DDR). We show that the function of FUS in DDR involves a direct interaction with histone deacetylase 1 (HDAC1), and that the recruitment of FUS to double stranded break (DSB) sites is important for proper DDR signaling. Remarkably, FUS proteins carrying familial ALS (fALS) mutations are defective in DDR and DNA repair, and show a diminished interaction with HDAC1. Moreover, increased DNA damage was also observed in human ALS patients harboring FUS mutations. Our findings suggest that an impaired DDR and DNA repair may contribute to the pathogenesis of neurodegenerative diseases linked to FUS mutations.
Proteins participate in various biological processes and can be harnessed to probe and control biological events selectively and reproducibly, but the genetic code limits the building block to 20 common amino acids for protein manipulation in living cells. The genetic encoding of unnatural amino acids will remove this restriction and enable new chemical and physical properties to be precisely introduced into proteins. Here we present new strategies for generating orthogonal tRNA-synthetase pairs, which made possible the genetic encoding of diverse unnatural amino acids in different mammalian cells and primary neurons. Using this new methodology, we incorporated unnatural amino acids with extended side chains into the K + channel Kv1.4, and found that the bulkiness of residues in the inactivation peptide is essential for fast channel inactivation, a finding that had not been possible using conventional mutagenesis. This technique will stimulate and facilitate new molecular studies using tailored unnatural amino acids for cell biology and neurobiology.
Key Points Perivascular cells maintain HSPCs ex vivo.
Non-coding variants in the human MIR137 gene locus increase schizophrenia risk at a genome-wide significance level. However, the functional consequence of these risk alleles is unknown. Here, we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms (SNPs) in MIR137, and observed increased MIR137 levels compared to major allele-carrying cells. We found that miR-137 gain-of-function causes downregulation of the presynaptic target genes, Complexin-1 (Cplx1), Nsf, and Synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain-of-function results in changes in synaptic vesicle pool distribution, impaired mossy fiber-LTP induction and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus.
This paper addresses the problem posed by complex, nonlinear controllers for power system load flows employing multi-terminal voltage source converter (VSC) HVDC systems. More realistic dc grid control strategies can thus be carefully considered in power flow analysis of ac/dc grids. Power flow methods for multi-terminal VSC-HVDC (MTDC) systems are analysed for different types of dc voltage control techniques and the weaknesses of present methods are addressed. As distributed voltage control is likely to be adopted by practical dc grids, a new generalized algorithm is proposed to solve the power flow problems with various non-linear voltage droops, and the method to incorporate this algorithm with ac power flow models is also developed. With five sets of voltage characteristics implemented, the proposed scheme is applied to a five-terminal test system and shows satisfactory performance. For a range of wind power variations and converter outages, post-contingency behaviours of the system under the five control scenarios are examined. The impact of these controls on the power flow solutions is assessed.
Using and engineering amyloid as nanomaterials are blossoming trends in bionanotechnology. Here, we show our discovery of an amyloid structure, termed "amyloid-like nanosheet," formed by a key amyloid-forming segment of Alzheimer's Aβ. Combining multiple biophysical and computational approaches, we proposed a structural model for the nanosheet that is formed by stacking the amyloid fibril spines perpendicular to the fibril axis. We further used the nanosheet for laboratorial retroviral transduction enhancement and directly visualized the presence of virus on the nanosheet surface by electron microscopy. Furthermore, based on our structural model, we designed nanosheet-forming peptides with different functionalities, elucidating the potential of rational design for amyloid-based materials with novel architecture and function.functional amyloid material | peptide self-assembly | nanosheet | retrovirus transduction | beta-amyloid N umerous proteins and polypeptides have been found to selfassemble into amyloid fibrils under certain conditions (1). They are associated not only with dozens of devastating diseases including Alzheimer's and Parkinson's diseases (2) but are integral to many biological processes such as hormone storage, signal transduction, and cell surface adhesion (3-5). Separate from the context of their parent proteins, synthesized peptide segments can self-assemble into amyloid-like fibrils in vitro as well (6, 7). Fibrils formed by diverse proteins and peptides all share a common cross-β structure, composed of interdigitated β-sheets termed "the zipper-like fibril spine" (8, 9). The self-assembly process is a consequence of backbone hydrogen bonding for the single β-sheet layer formation and side-chain interaction (e.g., hydrophobic interaction, π-stacking, and van der Waals) for pairing β-sheet layers together (10). Their highly repetitive and ordered architecture, in particular for the short peptide fibrils, exhibits favorable properties including high thermal stability and stiffness, biocompatibility, controllable self-assembly, surface patterning and integration of functionality, and inexpensive production by chemical synthesis (11-13). These exceptional properties promote the exploitation of amyloid fibril as an emerging class of bionanomaterials (14).Several studies have demonstrated that natural amyloidogenic and designed amphiphilic peptides are capable of self-assembling into nanostructures with topographies including fibril, film, nanotube, hydrogel, and liquid crystals (15-21), and these nanostructures have been used for nanowires, biosensors, 3D culturing, environmental carbon capture, retroviral gene transfer, light harvesting, and catalysis (22-26). Amyloid fibrils were also hybridized with other nanomaterials such as graphene and DNA origami in hopes of creating new properties and functions (27)(28)(29). In this study, we expand the amyloid material field's scope by the finding, structure characterization, and functionalization of a previously unidentified architecture-the amyloid-lik...
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