Article
Biology
Shenjie Wu, Nancy C. Hernandez Villegas, Daniel W. Sirkis, Iona Thomas-Wright, Richard Wade-Martins, Randy Schekman, Suzanne R. Pfeffer
Summary: This study reveals that DNAJC5 is localized to the cell membrane through palmitoylation and promotes the secretion of alpha-syn in HEK293T cells. Alpha-syn can also be actively translocated and sequestered in endosomal membrane compartments in a DNAJC5-dependent manner. The palmitoylation-deficient mutation in DNAJC5 can reduce the secretion of alpha-syn, but this can be reversed by the oligomerization of DNAJC5 induced by a membrane-targeting peptide fusion. The secretion of endogenous alpha-syn mediated by DNAJC5 is also observed in human neuroblastoma cell line SH-SY5Y and human-induced pluripotent stem cell-derived midbrain dopamine neurons.
Article
Neurosciences
Maria Ericsson, Victoria von Saucken, Andrew J. Newman, Lena Doehr, Camilla Hoesch, Tae-Eun Kim, Ulf Dettmer
Summary: The study found that specific engineered missense mutations disrupt the ability of alpha-synuclein to form native multimers, leading to the accumulation of excess monomers in lipid-membrane-rich inclusions associated with neurotoxicity. These inclusions may serve as precursors to Lewy bodies, and abnormal membrane tubulation could be a relevant aspect of aberrant alpha-synuclein behavior in cells.
Review
Clinical Neurology
Saranna Fanning, Dennis Selkoe, Ulf Dettmer
Summary: The neuronal protein alpha-synuclein plays a central role in Parkinson's disease and other progressive brain diseases, with strong associations to intracellular vesicle trafficking and lipid biology. Recent insights suggest a bidirectional relationship between alpha-S and vesicle trafficking and lipid-related genes in these diseases.
ACTA NEUROPATHOLOGICA
(2021)
Review
Biochemistry & Molecular Biology
Lennart Brodin, Dragomir Milovanovic, Silvio O. Rizzoli, Oleg Shupliakov
Summary: This review discusses recent data suggesting the protein alpha-synuclein as a component of the synaptic vesicle liquid phase, and considers possible implications of these data for disease.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Matthew K. Boag, Angus Roberts, Vladimir N. Uversky, Linlin Ma, Des R. Richardson, Dean L. Pountney
Summary: A major hallmark of Parkinson's disease is the destruction of dopaminergic neurons in the substantia nigra pars compacta. This destruction is preceded by the formation of Lewy bodies, composed of alpha-synuclein aggregates. The accumulation of alpha-synuclein, iron, and mitochondrial dysfunction affects the nigral neurons. The mechanisms underlying iron accumulation are not well understood. This review explores the relationship between iron regulation and alpha-synuclein and discusses the potential therapeutic targets in the context of Parkinson's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Ana Belen Uceda, Juan Frau, Bartolome Vilanova, Miquel Adrover
Summary: Human alpha-synuclein (α S) is an intrinsically disordered protein highly expressed in dopaminergic neurons. Its amyloid aggregates are considered a hallmark of Parkinson's disease (PD). The oxidation of alpha S's methionine residues (MetO) affects its affinity towards anionic micelles and synaptic-like vesicles, impairing its physiological function as a catalyst of vesicle clustering and fusion.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Dong-Yan Song, Lin Yuan, Na Cui, Cong Feng, Lanxia Meng, Xin-He Wang, Man Xiang, Di Liu, Chun Wang, Zhentao Zhang, Jia-Yi Li, Wen Li
Summary: Parkinson's disease is an age-related chronic neurological disorder characterized by the aggregation of alpha-synuclein. This study found that over-expression of human alpha-synuclein disrupts synaptic function by interfering with vesicle recycling, but this damage can be alleviated by the re-availment of SYNJ1.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Cell Biology
Anuttoma Ray, Parmender P. Mehta
Summary: Cx32 was found to be palmitoylated at cysteine 217 (C217) in cell line derived from prostate tumors, but mutating C217 to alanine had no effect on its function. Mutation of cysteine 280 and 283, only in combination, blocked the trafficking of Cx32 from the trans-Golgi network to the cell surface, leading to reduced stability.
CELLULAR SIGNALLING
(2021)
Article
Biochemistry & Molecular Biology
Gyeongji Yoo, Hyeong Jeon An, Sanghun Yeou, Nam Ki Lee
Summary: Research shows that alpha-Syn mutant oligomers have aberrant effects on VAMP2-embedded vesicles, with specific effects varying depending on the mutant types. This may provide clues to explain the pathological heterogeneity of familial PD.
MOLECULES AND CELLS
(2022)
Review
Biochemistry & Molecular Biology
Li Yang Tan, Kwan Hou Tang, Lynette Yu You Lim, Jia Xin Ong, Hyokeun Park, Sangyong Jung
Summary: alpha-synuclein is a protein strongly associated with the neuropathology observed in Parkinson's disease, dementia with Lewy bodies, and Alzheimer's disease. Mutations and modifications of alpha-syn interfere with its function, leading to abnormalities in presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Targeted therapies for alpha-syn are being explored, and the use of novel encapsulation technology may overcome existing challenges.
Article
Cell Biology
Yuxi Lin, Dai Ito, Je Min Yoo, Mi Hee Lim, Wookyung Yu, Yasushi Kawata, Young-Ho Lee
Summary: The aggregation of alpha-synuclein (alpha SN) under different conditions is closely related to synucleinopathies. This study examined the structural changes, binding properties, and amyloidogenicity of alpha SN mutants in two types of membranes. It was found that negatively charged membranes induced dramatic helical folding and amyloid generation of alpha SN, while neutral membranes had minimal effects.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Neurosciences
Charlotte F. Brzozowski, Baraa A. Hijaz, Vijay Singh, Nolwazi Z. Gcwensa, Kaela Kelly, Edward S. Boyden, Andrew B. West, Deblina Sarkar, Laura A. Volpicelli-Daley
Summary: The study reveals that LRRK2 kinase activity influences the presynaptic targeting of alpha-synuclein, suggesting potential mechanisms by which perturbations in alpha-synuclein localization mediated by LRRK2 could lead to pathology in both LRRK2-PD and idiopathic PD.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
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
Ana Belen Uceda, Juan Frau, Bartolome Vilanova, Miquel Adrover
Summary: Parkinson's disease is characterized by the degeneration of dopaminergic neurons and the accumulation of Lewy bodies. Previous studies have examined the molecular mechanism linking nitroxidation, aS aggregation, and PD, but the impact of nitroxidation on the physiological function of aS was unclear. Our research found that nitroxidation of Y39 lengthened the disordered stretch between two consecutive alpha-helices and prevented aS from functioning as a catalyst for the clustering and fusion of synaptic vesicles.
Article
Biochemistry & Molecular Biology
Shuang Li, Jing Liu, Heng Zhang, Zhepeng Sun, Zhu Ying, Yihan Wu, Jianhai Xu, Qun Liu
Summary: This study identified three GST proteins in Toxoplasma gondii, with GST2 playing a critical role in vesicle trafficking by localizing to the Golgi-endosomal system. Loss of TgGST2 led to incorrect localization and decreased expression of several secretory proteins, resulting in reduced invasion capacity and virulence to mice. The findings suggest that TgGST2 contributes to vesicle transport and plays a essential role in the parasite lytic cycle.
Editorial Material
Clinical Neurology
Gary P. H. Ho, Kate T. Brizzi, David M. Meredith, Edward R. Laws, Aaron L. Berkowitz
Article
Neurosciences
Gary P. H. Ho, Balakrishnan Selvakumar, Jun Mukai, Lynda D. Hester, Yuxuan Wang, Joseph A. Gogos, Solomon H. Snyder
Article
Multidisciplinary Sciences
Jiyoung Y. Cha, Hyo Jung Kim, Jung Hwan Yu, Jing Xu, Daham Kim, Bindu D. Paul, Hyeonjin Choi, Seyun Kim, Yoo Jeong Lee, Gary P. Ho, Feng Rao, Solomon H. Snyder, Jae-woo Kim
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2013)
Article
Biochemistry & Molecular Biology
Saranna Fanning, Aftabul Haque, Thibaut Imberdis, Valeriya Baru, M. Inmaculada Barrasa, Silke Nuber, Daniel Termine, Nagendran Ramalingam, Gary P. H. Ho, Tallie Noble, Jackson Sandoe, Yali Lou, Dirk Landgraf, Yelena Freyzon, Gregory Newby, Frank Soldner, Elizabeth Terry-Kantor, Tae-Eun Kim, Harald F. Hofbauer, Michel Becuwe, Rudolf Jaenisch, David Pincus, Clary B. Clish, Tobias C. Walther, Robert V. Farese, Supriya Srinivasan, Michael A. Weite, Sepp D. Kohlwein, Ulf Dettmer, Susan Lindquist, Dennis Selkoe
Article
Multidisciplinary Sciences
Thibaut Imberdis, Joseph Negri, Nagendran Ramalingam, Elizabeth Terry-Kantor, Gary P. H. Ho, Saranna Fanning, Georgia Stirtz, Tae-Eun Kim, Oren A. Levy, Tracy L. Young-Pearse, Dennis Selkoe, Ulf Dettmer
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2019)
Article
Biochemistry & Molecular Biology
Elizabeth Terry-Kantor, Arati Tripathi, Thibaut Imberdis, Zachary M. LaVoie, Gary P. H. Ho, Dennis Selkoe, Saranna Fanning, Nagendran Ramalingam, Ulf Dettmer
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)
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)
Article
Biochemistry & Molecular Biology
Gary P. H. Ho, Erin C. Wilkie, Andrew J. White, Dennis J. Selkoe
Summary: This study found that Synaptotagmin-11 (Syt11), a vesicle-trafficking protein, is genetically linked to Parkinson's disease (PD), and its palmitoylation disrupts alpha-synuclein homeostasis in neurons, promoting its aggregation and potentially contributing to the development of PD.
Article
Neurosciences
Alain Ndayisaba, Ariana T. Pitaro, Andrew S. Willett, Kristie A. Jones, Claudio Melo de Gusmao, Abby L. Olsen, Jisoo Kim, Eero Rissanen, Jared K. Woods, Sharan R. Srinivasan, Anna Nagy, Amanda Nagy, Merlyne Mesidor, Steven Cicero, Viharkumar Patel, Derek H. Oakley, Idil Tuncali, Katherine Taglieri-Noble, Emily C. Clark, Jordan Paulson, Richard C. Krolewski, Gary P. Ho, Albert Y. Hung, Anne-Marie Wills, Michael T. Hayes, Jason P. Macmore, Luigi Warren, Pamela G. Bower, Carol B. Langer, Lawrence R. Kellerman, Christopher W. Humphreys, Bonnie I. Glanz, Elodi J. Dielubanza, Matthew P. Frosch, Roy L. Freeman, Christopher H. Gibbons, Nadia Stefanova, Tanuja Chitnis, Howard L. Weiner, Clemens R. Scherzer, Sonja W. Scholz, Dana Vuzman, Laura M. Cox, Gregor Wenning, Jeremy D. Schmahmann, Peter Novak, Geoffrey S. Young, Mel B. Feany, Tarun Singhal, Vikram Khurana
Summary: The article introduces the process of developing a clinical trial-ready cohort of patients with Multiple System Atrophy (MSA) in an outpatient clinical setting, and the use of different tests and data collection methods to better understand disease progression and patient characteristics. Additionally, using induced pluripotent stem cell (iPSC) models from patient samples can provide more accurate information and help match patients with appropriate treatments.
Article
Multidisciplinary Sciences
Asif K. Mustafa, Manish Kumar, Balakrishnan Selvakumar, Gary P. H. Ho, Jeffrey T. Ehmsen, Roxanne K. Barrow, L. Mario Amzel, Solomon H. Snyder
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2007)
Article
Biochemistry & Molecular Biology
Gary P. H. Ho, Steven Margossian, Toshiyasu Taniguchi, Alan D. D'Andrea
MOLECULAR AND CELLULAR BIOLOGY
(2006)
Review
Oncology
PR Andreassen, GPH Ho, AD D'Andrea