Article
Biochemistry & Molecular Biology
Animesh Mondal, Sandip Dolui, Sukhamoy Dhabal, Shubham Kundu, Lopamudra Das, Ashish Bhattacharjee, Nakul C. Maiti
Summary: Parkinson's disease is associated with the aggregation of α-synuclein and the accumulation of amyloid in the substantia nigra region of the brain. This study identified two types of α-synuclein oligomers with different protein conformation and stability, and compared their toxic effects on neuronal cells. The lyophilized oligomer was highly toxic, while the heat-induced oligomer was less toxic. It was also found that the presence of molten globule-like conformation in the oligomer increased its toxicity to cultured neuronal cells.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Tatsuya Ikenoue, Miki Oono, Masatomo So, Hodaka Yamakado, Toshiaki Arata, Ryosuke Takahashi, Yasushi Kawata, Hiroaki Suga
Summary: A macrocyclic peptide, BD1, was identified using the RaPID system, which can interact with alpha Syn and inhibit fibril formation. This finding offers a promising approach for developing potential therapies against neurodegenerative diseases.
Article
Chemistry, Multidisciplinary
Ogonna Nwajiobi, Ashish Kumar Verma, Monika Raj
Summary: A novel rapid arene triazene strategy for macrocyclization of peptides is reported, which can generate a chromophoric triazene moiety at the site of cyclization within a minute. The resulting triazene cyclic peptide is highly stable but responsive to external stimuli and can undergo ring opening and re-cyclization. This method works with unprotected peptides and has been applied for the synthesis of monocycles and bicycles with various amino acid compositions. The stability of triazene cyclic peptides allows post-cyclization modification. This strategy has important applications in chemical biology, selective drug delivery, and identification of cyclic peptide hits.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Emma Lorentzon, Istvan Horvath, Ranjeet Kumar, Joana Isabel Rodrigues, Markus J. Tamas, Pernilla Wittung-Stafshede
Summary: Exposure to arsenic and cadmium alters alpha-synuclein amyloid fiber structures and distribution within yeast cells, reducing aggregate clearance and aggravating toxicity. In vitro studies suggest interactions between these heavy metals and alpha-synuclein may modulate the pathogenesis of Parkinson's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Genetics & Heredity
Blagovesta Popova, Dan Wang, Christina Paetz, Dagmar Akkermann, Diana F. Lazaro, Dajana Galka, Miriam Kolog Gulko, Markus T. Bohnsack, Wiebke Moebius, Katherine E. Bohnsack, Tiago F. Outeiro, Gerhard H. Braus
Summary: Research revealed that the expression of alpha-synuclein affects transcription levels in yeast and human cells, with the nucleolar DEAD-box helicase Dbp4 identified as a key modulator of alpha-synuclein toxicity. Interaction between alpha-synuclein and Dbp4/DDX10 leads to sub-cellular exclusion from the nucleolus and accumulation of toxic oligomeric species, presenting a novel perspective on Parkinson's disease complexity.
Article
Clinical Neurology
Ito Kawakami, Atsuko Motoda, Masashi Hashimoto, Aki Shimozawa, Masami Masuda-Suzukake, Reiko Ohtani, Mina Takase, Mari Kumashiro, Kazuyuki Samejima, Masato Hasegawa
Summary: The study found that synthetic human alpha-syn fibrils can spread throughout the brain of macaque monkeys via projection, association, and commissural fibers, although the progression of alpha-syn pathology is limited.
Article
Chemistry, Multidisciplinary
Yiyin Xia, Janet To, Ning-Yu Chan, Side Hu, Heng Tai Liew, Seetharamsing Balamkundu, Xiaohong Zhang, Julien Lescar, Surajit Bhattacharjya, James P. Tam, Chuan-Fa Liu
Summary: This study found that Asn(OH) is an unnatural substrate for PALs, and successfully synthesized a new MMP2 inhibitor cyclic peptide using Asn(OH)-mediated cyclization, with the hydroxamic acid moiety as the key pharmacophore. Several bioactive Asp-containing cyclic peptides were also synthesized using this approach, demonstrating the effectiveness of substrate engineering in expanding the application of PAL ligation in the synthesis of therapeutic cyclic peptides.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Review
Clinical Neurology
Wouter Peelaerts, Veerle Baekelandt
Summary: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are synucleinopathies characterized by the intracellular aggregation of alpha-synuclein. The cellular tropism of synuclein pathology differs in these disorders, with PD and DLB showing aggregates in neurons and MSA showing aggregates in oligodendrocytes. Studies have found unique molecular signatures of fibrillar alpha-synuclein in experimental models and human brain, suggesting that the structure of these fibrils may be influenced by their cellular environment. The cellular host environment and in vivo transmission routes may play a role in the development of alpha-synuclein strains. This finding has implications for preclinical studies and the development of biomarkers and therapeutic strategies.
Article
Biophysics
Barbara Claro, Antonio Peon, Eva Gonzalez-Freire, Erik Goormaghtigh, Manuel Amorin, Juan R. Granja, Rebeca Garcia-Fandino, Margarida Bastos
Summary: Antimicrobial D,L-alpha-cyclic peptides have shown to form complex macromolecular assemblies in the presence of membranes, depending on the negatively charged content of the membrane and lipid/peptide ratio. Experimental techniques and simulations suggest that CPs can self-assemble at the lipid surface into nanotubes or micellar aggregates, revealing possible mechanisms of action involving membrane segregation or disintegration.
COLLOIDS AND SURFACES B-BIOINTERFACES
(2021)
Article
Biochemistry & Molecular Biology
G. Chandrasekhar, E. Srinivasan, S. Nandhini, G. Pravallika, G. Sanjay, R. Rajasekaran
Summary: Parkinson's disorder (PD) is characterized by the degeneration of motor nerves, causing uncoordinated movements and tremors. The abnormal alpha-synuclein (alpha-syn) protein is responsible for triggering PD by forming toxic amyloid aggregates in motor neurons. In this study, we developed a tripeptide, VAV, based on the aggregation-prone region of alpha-syn, which effectively mitigated the formation of beta-sheet-rich amyloid fibrils. Molecular simulations showed that VAV altered the pathogenic structural dynamics of alpha-syn, suggesting its potential to alleviate neurotoxicity. This study highlights the therapeutic potential of VAV tripeptide in reducing the harmful effects of PD.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Multidisciplinary
Masanobu Nagano, Yichao Huang, Richard Obexer, Hiroaki Suga
Summary: This study presents a one-pot ribosomal synthesis method for the construction of macrocyclic depsipeptides, based on the SPCG motif. The ribosomal synthesis of linear peptides containing the SPCG motif with a backbone acyl donor thioester results in spontaneous conversion to corresponding cyclic depsipeptides.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Review
Biochemistry & Molecular Biology
Alexandra Bluhm, Sarah Schrempel, Stephan von Hoersten, Anja Schulze, Steffen Rossner
Summary: In Parkinson's disease, the aggregation of alpha-synuclein is a neuropathological hallmark, but the mechanisms behind this aggregation are not fully understood. Recent research suggests that oxidative stress induced by metal ions and post-translational modifications can affect the conformation of alpha-synuclein, influencing its propensity for aggregation and neurotoxicity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Meiru Song, Ge Liu, Yichang Liu, Ziwei Cheng, Haili Lin, Jianyong Liu, Zaisheng Wu, Jinping Xue, Wanjin Hong, Mingdong Huang, Jinyu Li, Peng Xu
Summary: This study proposes a strategy to address the limitations of AMPs as antitumor agents by conjugating them with porphyrins, which bind to albumin and enhance the antitumor efficacy of AMPs. The conjugation also reduces the fast renal clearance and systemic toxicities of AMPs, confirming the design strategy's success.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Clinical Neurology
Yi-Qun Yan, Jia-Li Pu, Ran Zheng, Yi Fang, Lu-Yan Gu, Tao Guo, Xiao-Li Si, Cheng Zhou, Ying Chen, Yi Liu, Xiao-Jun Guan, Xiao-Jun Xu, Ya-Ping Yan, Xin-Zhen Yin, Min-Ming Zhang, Zhi-Hua Tao, Bao-Rong Zhang
Summary: The study suggests that both plasma total exosomal alpha-Syn and neural-derived exosomal alpha-Syn were elevated in Parkinson's disease (PD) patients, while only neural-derived exosomal alpha-Syn was elevated in probable idiopathic rapid eye movement sleep behavior disorder (pRBD) patients. Additionally, the adaptor protein of inflammasome ASC is correlated with alpha-Syn and may play a role in synucleinopathy.
EUROPEAN JOURNAL OF NEUROLOGY
(2022)
Article
Neurosciences
Dylan J. Dues, Yue Ma, An Phu Tran Nguyen, Alina Offerman, Ian Beddows, Darren J. Moore
Summary: Leucine-rich repeat kinase 2 (LRRK2) and alpha-synuclein play important roles in the pathobiology of Parkinson's disease (PD), but the interaction between LRRK2 and alpha-synuclein in the accumulation of pathological alpha-synuclein remains unclear. Through experiments, it was found that LRRK2 does not have a significant impact on alpha-synuclein pathology in the mouse forebrain, but may contribute to alpha-synuclein-induced neuroinflammation.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Engineering, Biomedical
Chenglong Xie, Xu-Xu Zhuang, Zhangming Niu, Ruixue Ai, Sofie Lautrup, Shuangjia Zheng, Yinghui Jiang, Ruiyu Han, Tanima Sen Gupta, Shuqin Cao, Maria Jose Lagartos-Donate, Cui-Zan Cai, Li-Ming Xie, Domenica Caponio, Wen-Wen Wang, Tomas Schmauck-Medina, Jianying Zhang, He-ling Wang, Guofeng Lou, Xianglu Xiao, Wenhua Zheng, Konstantinos Palikaras, Guang Yang, Kim A. Caldwell, Guy A. Caldwell, Han-Ming Shen, Hilde Nilsen, Jia-Hong Lu, Evandro F. Fang
Summary: This study utilized machine learning and a cross-species approach to identify and validate two potent mitophagy inducers. These compounds improved neuronal survival and functionality, abrogated pathology in AD models, and enhanced memory.
NATURE BIOMEDICAL ENGINEERING
(2022)
Article
Neurosciences
Saranna Fanning, Haley Cirka, Jennifer L. Thies, Jooyoung Jeong, Sarah M. Niemi, Joon Yoon, Gary P. H. Ho, Julian A. Pacheco, Ulf Dettmer, Lei Liu, Clary B. Clish, Kevin J. Hodgetts, John N. Hutchinson, Christina R. Muratore, Guy A. Caldwell, Kim A. Caldwell, Dennis Selkoe
Summary: Study finds targeting lipid metabolism can reverse pathological phenotypes of synucleinopathy and identifies lipase enzyme LIPE as a potential therapeutic target.
NPJ PARKINSONS DISEASE
(2022)
Review
Biochemistry & Molecular Biology
Melanie Mew, Kim A. Caldwell, Guy A. Caldwell
Summary: The exponential growth of DNA sequencing data has provided new opportunities for discovering the role of SNPs in neurological diseases. Invertebrate models, such as flies and worms, have proven to be valuable tools for classifying genetic variants and accelerating drug development for these diseases.
HUMAN MOLECULAR GENETICS
(2022)
Article
Pathology
Jared K. Woods, Hart G. Lidov, Keith L. Ligon, Sandro Santagata, Susan N. Chi, Kee Kiat Yeo, Sanda Alexandrescu
Summary: This study found immune activity in central nervous system germ cell tumors (GCTs) and suggested that the expression of PD-L1 and PD-1 may have implications for treatment. The choriocarcinoma subtype in non-germinomatous GCTs may benefit the most from immune checkpoint blockade.
Article
Oncology
Abrar Choudhury, William C. Chen, Calixto-Hope G. Lucas, James C. Bayley, Akdes S. Harmanci, Sybren L. N. Maas, Sandro Santagata, Tiemo Klisch, Arie Perry, Wenya Linda Bi, Felix Sahm, Akash Patel, Stephen T. Magill, David R. Raleigh
Summary: This study reanalyzed the DNA methylation profiles of 565 meningiomas and classified them into Merlin-intact, Immune-enriched, and Hypermitotic DNA methylation groups. RNA sequencing revealed two subgroups of Hypermitotic meningiomas with differential enrichment of FOXM1 target genes. Further analysis showed that these subgroups were concordant with Proliferative and Hypermetabolic meningiomas. Adding DNA methylation subgroups to clinical models improved the prediction of postoperative outcomes.
Article
Genetics & Heredity
Anthony L. Gaeta, J. Brucker Nourse, Karolina Willicott, Luke E. Mckay, Candice M. Keogh, Kylie Peter, Shannon N. Russell, Shusei Hamamichi, Laura A. Berkowitz, Kim A. Caldwell, Guy A. Caldwell
Summary: The fine-tuning of gene expression is crucial for cellular processes, and dysregulation can lead to disease. This study examines the effects of gene silencing defects on Parkinson's disease in Caenorhabditis elegans, and identifies specific microRNAs and their targets that modulate neurodegeneration. The findings suggest potential therapeutic targets for PD intervention.
Article
Biochemistry & Molecular Biology
Jia-Ren Lin, Shu Wang, Shannon Coy, Yu -An Chen, Clarence Yapp, Madison Tyler, Maulik K. Nariya, Cody N. Heiser, Ken S. Lau, Sandro Santagata, Peter K. Sorger
Summary: We used advanced imaging techniques, 3D reconstruction, spatial statistics, and machine learning to identify cell types and states associated with diagnostic and prognostic features in colorectal cancer. We found that at the tumor invasive margin, T cell suppression involves multiple cell types and that seemingly localized features such as tertiary lymphoid structures are interconnected and have graded molecular properties. These findings challenge the notion that discrete changes in tumor state are most important, demonstrating the presence of large-scale morphological and molecular gradients.
Article
Multidisciplinary Sciences
J. Brucker Nourse, Shannon N. Russell, Nathan A. Moniz, Kylie Peter, Lena M. Seyfarth, Madison Scott, Han-A Park, Kim A. Caldwell, Guy A. Caldwell
Summary: This study investigates the TNK2 gene variants in Parkinson's disease (PD) patients and their potential impact on dopaminergic neurodegeneration. The findings suggest that TNK2 dysfunction may contribute to PD, possibly through sustained or aberrant activity. The study also highlights the importance of TNK2 and its ortholog SID-3 in coordinating dopaminergic and epigenetic signaling. Experimental results using Caenorhabditis elegans and rat primary neurons demonstrate the neuroprotective effects of TNK2 inhibition and NEDD4 activation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biology
Clarence Yapp, Edward Novikov, Won-Dong Jang, Tuulia Vallius, Yu-An Chen, Marcelo Cicconet, Zoltan Maliga, Connor A. Jacobson, Donglai Wei, Sandro Santagata, Hanspeter Pfister, Peter K. Sorger
Summary: This paper reports two findings that substantially improve image segmentation of tissues using a range of machine learning architectures. The inclusion of intentionally defocused and saturated images in training data and imaging the nuclear envelope using an antibody cocktail both significantly improve segmentation. These approaches have a positive impact on a wide range of tissue types and may have applications in image processing outside of microscopy.
COMMUNICATIONS BIOLOGY
(2022)
Article
Cell Biology
Jennifer L. Thies, Karolina Willicott, Maici L. Craig, Madeline R. Greene, Cassandra N. DuGay, Guy A. Caldwell, Kim A. Caldwell
Summary: Exposure to S. ven metabolites enhances oxidative stress and mitochondrial dysfunction in C. elegans, leading to dopaminergic neurodegeneration. Gene analysis reveals that a majority of the differentially expressed genes are associated with the transcription factor DAF-16 (FOXO). Exposure to S. ven metabolites also increases XO activity in C. elegans.
Article
Multidisciplinary Sciences
Anthony L. Gaeta, Karolina Willicott, Corey W. Willicott, Luke E. Mckay, Candice M. Keogh, Tyler J. Altman, Logan C. Kimble, Abigail L. Yarbrough, Kim A. Caldwell, Guy A. Caldwell
Summary: Failure of protective cellular processes and misfolded protein-associated stress contribute to the loss of dopamine neurons in Parkinson's disease. The microbiome has been found to play a role in PD, and C. elegans is used as a model to study gene expression and neurodegeneration in transgenic animals. Different gene expression and neuroprotective responses were observed in C. elegans strains overexpressing alpha-synuclein when fed different bacterial food sources. Genetic analysis revealed the involvement of the dsRNA-mediated gene silencing machinery and endopeptidase activity in neuroprotection.
Article
Developmental Biology
Lindsey A. Starr, Luke E. McKay, Kylie N. Peter, Lena M. Seyfarth, Laura A. Berkowitz, Kim A. Caldwell, Guy A. Caldwell
Summary: Reduced expression of xdh-1, the ortholog of human xanthine dehydrogenase (XDH), is protective against alpha-synuclein-induced dopaminergic neurodegeneration. The worm ortholog of the human ABCG2 transporter, WHT-2, is the rate-limiting factor in this system. Modifying specific targets of RNA editing may represent a promising therapeutic strategy for Parkinson's disease.
JOURNAL OF DEVELOPMENTAL BIOLOGY
(2023)
