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How do neurons age?A focused review on the aging of the microtubular cytoskeleton

Neural Regeneration Research 2024年第9期19卷 1899-1907页

作者： Brad Richardson Thomas Goedert Shmma Quraishe Katrin Deinhardt Amritpal Mudher school of biological sciences University of SouthamptonSouthamptonUK Institute of Developmental and Regenerative Medicine University of OxfordOxfordUK

Aging is the leading risk factor for Alzheimer’s disease and other neurodegenerative diseases. We now understand that a breakdown in the neuronal cytoskeleton, mainly underpinned by protein modifications leading to the destabilization of microtubules, is central to the pathogenesis of Alzheimer’s disease. This is accompanied by morphological defects across the somatodendritic compartment, axon, and synapse. However, knowledge of what occurs to the microtubule cytoskeleton and morphology of the neuron during physiological aging is comparatively poor. Several recent studies have suggested that there is an age-related increase in the phosphorylation of the key microtubule stabilizing protein tau, a modification, which is known to destabilize the cytoskeleton in Alzheimer’s disease. This indicates that the cytoskeleton and potentially other neuronal structures reliant on the cytoskeleton become functionally compromised during normal physiological aging. The current literature shows age-related reductions in synaptic spine density and shifts in synaptic spine conformation which might explain age-related synaptic functional deficits. However, knowledge of what occurs to the microtubular and actin cytoskeleton, with increasing age is extremely limited. When considering the somatodendritic compartment, a regression in dendrites and loss of dendritic length and volume is reported whilst a reduction in soma volume/size is often seen. However, research into cytoskeletal change is limited to a handful of studies demonstrating reductions in and mislocalizations of microtubule-associated proteins with just one study directly exploring the integrity of the microtubules. In the axon, an increase in axonal diameter and age-related appearance of swellings is reported but like the dendrites, just one study investigates the microtubules directly with others reporting loss or mislocalization of microtubule-associated proteins. Though these are the general trends reported, there are clear disparities between model organisms and brain

关键词： age-related changes aging cytoskeleton microtubules neuronal morphology

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Reproductive ecology of the black rat (Rattus rattus) in Madagascar: the influence of density-dependent and -independent effects

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Integrative Zoology 2024年第1期19卷 66-86页

作者： Kathryn SCOBIE Soanandrasana RAHELINIRINA Voahangy SOARIMALALA Fehivola Mandanirina ANDRIAMIARIMANANA Corinne RAHAINGOSOAMAMITIANA Toky RANDRIAMORIA Soloandry RAHAJANDRAIBE Xavier LAMBIN Minoarisoa RAJERISON Sandra TELFER school of biological sciences University of AberdeenAberdeenUK Plague Unit Institut Pasteur de MadagascarAntananarivoMadagascar Association Vahatra AntananarivoMadagascar

The black rat(Rattus rattus)poses a severe threat to food security and public health in Madagascar,where it is a major cause of pre-and post-harvest crop losses and an important reservoir for many zoonotic diseases,including plague.Elsewhere,ecologically based rodent management(EBRM)strategies have been developed using ecologi-cal information to inform decisions on where and when to target control.EBRM could deliver improved health and well-being outcomes in Madagascar if adapted to the local ecological context.Using data collected from removal studies,we explored spatio-temporal patterns in the breeding activity of the black rat(R.rattus)in domestic and agricultural habitats across Madagascar and investigated to what extent these trends are influenced by rainfall and rat density.We identified clear spatio-temporal variation in the seasonality of R.rattus reproduction.Reproduction was highly seasonal both inside and outside of houses,but seasonal trends varied between these two habitats.Sea-sonal trends were explained,in part,by variation in rainfall;however,the effect of rainfall on reproductive rates did itself vary by season and habitat type.A decline in breeding intensity with increasing rat density was recorded outside of houses.This has important implications for control,as populations may compensate for removal through increased reproduction.We recommend that sustained control initiated before the main breeding season,combined with improved hygiene and adequate rodent-proofing in homes and grain stores,could curtail population growth and reduce pre-and post-harvest losses provided that these measures overcome the compensatory response of rodent populations.

关键词： Madagascar Rattus rattus reproductive ecology rodent control

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New insights into nitric oxide biosynthesis underpin lateral root development

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Molecular Plant 2024年第5期17卷 691-693页

作者： Kapuganti Jagadis Gupta Nidhi Yadav Aprajita Kumari Gary J.Loake National Institute for Plant Genome Research Aruna Asaf Ali MargNew Delhi 110070India Institute of Molecular Plant sciences School of Biological SciencesUniversity of EdinburghEH93BF EdinburghUK Centre for Engineering Biology School of Biological SciencesUniversity of EdinburghEH93BF EdinburghUK

In recent years,nitric oxide(NO)has emerged as a key redox signaling molecule in plants functioning in the regulation of key developmental programs and the orchestration of responses to a plethora of environmental cues(Kolbert et al.,2019).The predominant route for the transfer of NO bioactivity is through S-nitrosylation,the addition of an NO moiety to a protein cysteine thiol to form an S-nitrosothiol(Yun et al.,2011).Specificity for this process is established by the structural constraints imposed by tertiary protein structure in gating access to given cysteine redox switches and associated proteins that can either facilitate the addition or removal of the NO moiety at these residues(Umbreen et al.,2018).

关键词： moiety addition redox

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A phase separation-fortified bi-specific adaptor for conditional tumor killing

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Science China(Life sciences) 2024年第7期67卷 1385-1397页

作者： Yuyan Liu Yuting Zhu Weifan Xu Pilong Li State Key Laboratory of Membrane Biology Frontier Research Center for Biological StructureTsinghua University-Peking University Joint Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China

A common approach in therapeutic protein development involves employing synthetic ligands with multivalency,enabling sophisticated control of signal transduction.Leveraging the emerging concept of liquid-liquid phase separation(LLPS)and its ability to organize cell surface receptors into functional compartments,we herein have designed modular ligands with phase-separation modalities to engineer programmable interreceptor communications and precise control of signal pathways,thus inducing the rapid,potent,and specific apoptosis of tumor cells.Despite their simplicity,these“triggers”,named phase-separated Tumor Killers(hereafter referred to as psTK),are sufficient to yield interreceptor clustering of death receptors(represented by DR5)and tumor-associated receptors,with notable features:LLPSmediated robust high-order organization,well-choreographed conditional activation,and broad-spectrum capacity to potently induce apoptosis in tumor cells.The development of novel therapeutic proteins with phase-separation modalities showcases the power of spatially reorganizing signal transduction.This approach facilitates the diversification of cell fate and holds promising potential for targeted therapies against challenging tumors.

关键词： phase separation therapeutic proteins receptor-ligand interactions DR5 tumor apoptosis

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Antisense therapy:a potential breakthrough in the treatment of neurodegenerative diseases

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Neural Regeneration Research 2024年第5期19卷 1027-1035页

作者： Roberta Romano Cecilia Bucci Department of biological and Environmental sciences and Technologies(DiSTeBA) University of SalentoLecceItaly

Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.

关键词： Alzheimer’s disease amyotrophic lateral sclerosis antisense oligonucleotide Huntington’s disease neurodegenerative disorders Parkinson’s disease siRNA

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Unveiling the atomic-scale transition between light harvesting and photoprotective states in plant photosynthesis

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Science China Chemistry 2024年第5期67卷 1375-1377页

作者： Alexander V.Ruban school of biological and Behavioural sciences Queen Mary University of LondonLondon E14NSUK

Non-photochemical chlorophyll fluorescence quenching(NPQ) stands as a cornerstone in the realm of photosynthesis research, attracting generations of dedicated scientists in their quest to unravel its mysteries. This mechanism, crucial for safeguarding photosynthesis, plays a pivotal role in regulating light harvesting, particularly in oxygenic photosynthesis where the oxygen-evolving photosystem II (PSII)is susceptible to photodamage [1].

关键词： harvesting protective attracting

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Visualizing Wallerian degeneration in the corticospinal tract after sensorimotor cortex ischemia in mice

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Neural Regeneration Research 2024年第3期19卷 636-641页

作者： Jiao Mu Liufang Hao Zijue Wang Xuyang Fu Yusen Li Fei Hao Hongmei Duan Zhaoyang Yang Xiaoguang Li Beijing Key Laboratory for Biomaterials and Neural Regeneration School of Biological Science and Medical EngineeringBeihang UniversityBeijingChina Department of Neurobiology School of Basic Medical SciencesCapital Medical UniversityBeijingChina

Stroke can cause Wallerian degeneration in regions outside of the brain,particularly in the corticospinal tract.To investigate the fate of major glial cells and axons within affected areas of the corticospinal tract following stroke,we induced photochemical infarction of the sensorimotor cortex leading to Wallerian degeneration along the full extent of the corticospinal tract.We first used a routine,sensitive marker of axonal injury,amyloid precursor protein,to examine Wallerian degeneration of the corticospinal tract.An antibody to amyloid precursor protein mapped exclusively to proximal axonal segments within the ischemic cortex,with no positive signal in distal parts of the corticospinal tract,at all time points.To improve visualization of Wallerian degeneration,we next utilized an orthograde virus that expresses green fluorescent protein to label the corticospinal tract and then quantitatively evaluated green fluorescent protein-expressing axons.Using this approach,we found that axonal degeneration began on day 3 post-stroke and was almost complete by 7 days after stroke.In addition,microglia mobilized and activated early,from day 7 after stroke,but did not maintain a phagocytic state over time.Meanwhile,astrocytes showed relatively delayed mobilization and a moderate response to Wallerian degeneration.Moreover,no anterograde degeneration of spinal anterior horn cells was observed in response to Wallerian degeneration of the corticospinal tract.In conclusion,our data provide evidence for dynamic,pathogenic spatiotemporal changes in major cellular components of the corticospinal tract during Wallerian degeneration.

关键词： corticospinal tract green fluorescent protein microglia spinal anterior horn cells stroke virus trace Wallerian degeneration

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How variable progenitor clones construct a largely invariant neocortex

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National Science Review 2024年第1期11卷 129-144页

作者： Zhongfu Shen Jiajun Yang Qiangqiang Zhang Kuiyu Wang Xiaohui Lv Xiaolin Hu Jian Ma Song-Hai Shi New Cornerstone Science Laboratory IDG/McG overn Institute for Brain Research Tsinghua-Peking Center for Life Sciences Beijing Frontier Research Center for Biological Structure School of Life Sciences Tsinghua University Department of Computer sciences Tsinghua University College of Life sciences Nankai University Chinese Institute for Brain Research

The neocortex contains a vast collection of diverse neurons organized into distinct layers. While nearly all neocortical neurons are generated by radial glial progenitors(RGPs), it remains largely unclear how a complex yet organized neocortex is constructed reliably and robustly. Here, we show that the division behavior and neuronal output of RGPs are highly constrained with patterned variabilities to support the reliable and robust construction of the mouse neocortex. The neurogenic process of RGPs can be well-approximated by a consistent Poisson-like process unfolding over time, producing deep to superficial layer neurons progressively. The exact neuronal outputs regarding layer occupation are variable; yet, this variability is constrained systematically to support all layer formation, largely reflecting the variable intermediate progenitor generation and RGP neurogenic entry and exit timing differences. Together, these results define the fundamental features of neocortical neurogenesis with a balanced reliability and variability for the construction of the complex neocortex.

关键词： neocortex radial glial progenitor intermediate progenitor neurogenesis clonal variability layer formation

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Higher levels of the lipophilic antioxidants coenzyme Q_(10) and vitamin E in long-lived termite queens than in short-lived workers

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Insect Science 2024年第1期31卷 201-210页

作者： Eisuke Tasaki Yorihiro Yamamoto Yoshihito Iuchi Department of biological Chemistry Graduate School of Sciences and Technology for InnovationYamaguchi UniversityYamaguchiJapan school of Bioscience and Biotechnology Tokyo University of TechnologyHachiojiTokyoJapan

Termite queens and kings live longer than nonreproductive workers.Several molecular mechanisms contributing to their long lifespan have been investigated;however,the underlying biochemical explanation remains unclear.Coenzyme Q(CoQ),a component of the mitochondrial electron transport chain,plays an essential role in the lipophilic antioxidant defense system.Its beneficial effects on health and longevity have been well studied in several organisms.Herein,we demonstrated that long-lived termite queens have significantly higher levels of the lipophilic antioxidant CoQ_(10) than workers.Liquid chromatography analysis revealed that the levels of the reduced form of CoQ_(10) were 4 fold higher in the queen's body than in the worker's body.In addition,queens showed 7 fold higher levels of vitamin E,which plays a role in antilipid peroxidation along with CoQ,than workers.Furthermore,the oral administration of CoQ_(10) to termites increased the CoQ_(10) redox state in the body and their survival rate under oxidative stress.These findings suggest that CoQ_(10) acts as an efficient lipophilic antioxidant along with vitamin E in long-lived termite queens.This study provides essential biochemical and evolutionary insights into the relationship between CoQ_(10) concentrations and termite lifespan extension.

关键词： antioxidant defense system coenzyme Q termite queens vitamin E

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Broad-spectrum ginsentides are principal bioactives in unraveling the cure-all effects of ginseng

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Acta Pharmaceutica Sinica B 2024年第2期14卷 653-666页

作者： Shining Loo Antony Kam Bamaprasad Dutta Xiaohong Zhang Nan Feng Siu Kwan Sze Chuan-Fa Liu Xiaoliang Wang James P.Tam school of biological sciences Nanyang Technological UniversitySingapore 637551Singapore Academy of Pharmacy Xi’an Jiaotong-Liverpool UniversitySuzhou 215123China Department of biological sciences Xi’an Jiaotong-Liverpool UniversitySuzhou 215123China Institute of Materia Medica Chinese Academy of Medical SciencesBeijing 100050China Department of Health sciences Brock UniversityNiagara RegionON L2S 3A1Canada

Stress and illness connection is complex and involves multiple physiological systems.Panax ginsengs,reputed for their broad-spectrum“cure-all”effect,are widely prescribed to treat stress and related illnesses.However,the identity of ginseng’s“cure-all”medicinal compounds that relieve stress remains unresolved.Here,we identify ginsentides as the principal bioactives that coordinate multiple systems to restore homeostasis in response to stress.Ginsentides are disulfide-rich,cell-penetrating and proteolytic-stable microproteins.Using affinity-enrichment mass spectrometry target identification together with in vitro,ex vivo and in vivo validations,we show that highly purified or synthetic ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells via intracellular PI3K/Akt signaling pathway,alleviate a1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of aorta,decrease monocyte adhesion to endothelial cells via CD166/ESAM/CD40 and inhibit P2Y12 receptors to reduce platelet aggregation.Orally administered ginsentides were effective in animal models to reduce ADP-induced platelet aggregation,to prevent collagen and adrenalineinduced pulmonary thrombosis as well as anti-stress behavior of tail suspension and forced swimming tests in mice.Together,these results strongly suggest that ginsentides are the principal panacea compounds of ginsengs because of their ability to target multiple extra-and intra-cellular proteins to reverse stress-induced damages.

关键词： Ginseng Cysteine-rich peptides Microproteins Cure-all Stress Homeostasis

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