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)
Review
Biochemistry & Molecular Biology
Abbie T. Rodger, Maryam A. L. Nasser, Wayne G. Carter
Summary: Currently, there are no pharmacological treatments that can completely stop or reverse the progression of Parkinson's Disease (PD). Therefore, there is a need for neuroprotective therapies. This systematic review examines the effectiveness of anti-a-synuclein (a-syn) therapies in preventing PD progression in preclinical models and human clinical trials. The review found that novel preclinical anti-a-syn therapeutics reduced a-syn aggregations and protected against dopaminergic neuronal loss. Completed clinical trials showed significant tolerability and efficacy in reducing a-syn and minimal adverse effects. Overall, this review highlights the potential of anti-a-syn therapies in both preclinical and clinical settings to reduce a-syn accumulation and potentially slow down PD progression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Md Ezazul Haque, Mahbuba Akther, Shofiul Azam, In-Su Kim, Yuxi Lin, Young-Ho Lee, Dong-Kug Choi
Summary: In Parkinson's disease, the aggregated alpha-synuclein in Lewy bodies and mitochondrial dysfunction play crucial roles in neurodegeneration, with interactions between aggregated alpha-synuclein and mitochondria potentially leading to neuronal loss, making it an emerging drug target for Parkinson's disease treatment.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Review
Neurosciences
Tiago Fleming Outeiro
Summary: In protein aggregation disorders, oligomeric species may be more toxic than fibrillar forms. Definitive data on the nature of toxic species are lacking due to difficulties in detecting and defining protein aggregate species.
MOLECULAR NEUROBIOLOGY
(2021)
Article
Clinical Neurology
Linbo Wang, Cheng Zhou, Wei Zhang, Minming Zhang, Wei Cheng, Jianfeng Feng
Summary: This study investigated the relationships between cortical and subcortical mean diffusivity (MD), clinical progression, and fluid biomarkers in Parkinson's disease (PD). The results showed significant associations between MD values and the annual rate of changes in clinical scores. MD was also correlated with levels of various fluid biomarkers. These findings suggest that microstructural properties could be useful for stratifying PD patients with fast clinical progression.
Article
Neurosciences
Briana R. De Miranda, Sandra L. Castro, Emily M. Rocha, Christopher R. Bodle, Katrina E. Johnson, J. Timothy Greenamyre
Summary: Research suggests that certain industrial compounds, such as organic solvents, may interact with the genetic mutation in the LRRK2 gene, increasing the risk of Parkinson's disease (PD).
NEUROBIOLOGY OF DISEASE
(2021)
Article
Multidisciplinary Sciences
Aitor Franco, Pablo Gracia, Adai Colom, Jose D. Camino, Jose Angel Fernandez-Higuero, Natalia Orozco, Alexander Dulebo, Leonor Saiz, Nunilo Cremades, Jose M. G. Vilar, Adelina Prado, Arturo Muga
Summary: Research shows that the Hsc70-based disaggregase system preferentially breaks down toxic oligomers and short fibrils, while its activity against larger, less toxic amyloids is severely impaired. This behavior is the result of an all-or-none abrupt solubilization of individual aggregates.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Maria Dolores Perez-Carrion, Inmaculada Posadas, Javier Solera, Valentin Cena
Summary: This review summarizes the main pathological mutations in LRRK2 that contribute to Parkinson's disease and discusses the different cellular and therapeutic strategies to correct LRRK2 homeostasis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Jennifer Ramirez, Samantha X. Pancoe, Elizabeth Rhoades, E. James Petersson
Summary: This article investigates the effects of interactions between the small neuronal protein alpha-synuclein and lipids on aggregation. By analyzing a comprehensive collection of experimental data, the general trends of lipid structure influencing aggregation are identified, providing a resource for interpreting the effects of lipids on aggregation and potentially serving as inputs for computational models.
Article
Neurosciences
Linn Streubel-Gallasch, Veronica Giusti, Michele Sandre, Isabella Tessari, Nicoletta Plotegher, Elena Giusto, Anna Masato, Ludovica Iovino, Ilaria Battisti, Giorgio Arrigoni, Derya Shimshek, Elisa Greggio, Marie-Eve Tremblay, Luigi Bubacco, Anna Erlandsson, Laura Civiero
Summary: This study compared the ability of astrocytes carrying PD-linked gene mutations with normal astrocytes in handling α-synuclein, finding a decreased clearance capacity in mutant cells linked to a loss of function in AnxA2.
MOLECULAR NEUROBIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Rachael J. Chandler, Susanna Cogo, Patrick A. Lewis, Eva Kevei
Summary: The challenge in Parkinson's disease research lies in the complex genetic architecture, with Caenorhabditis elegans serving as a beneficial model to uncover molecular and cellular mechanisms of the disease. This review highlights the advantages of using C. elegans in studying PD, focusing on how it contributes to understanding PD genetics and pathogenesis.
BIOSCIENCE REPORTS
(2021)
Article
Medicine, Research & Experimental
Marc Emmenegger, Elena De Cecco, Marian Hruska-Plochan, Timo Eninger, Matthias M. Schneider, Melanie Barth, Elena Tantardini, Pierre de Rossi, Mehtap Bacioglu, Rebekah G. Langston, Alice Kaganovich, Nora Bengoa-Vergniory, Andres Gonzalez-Guerra, Merve Avar, Daniel Heinzer, Regina Reimann, Lisa M. Haesler, Therese W. Herling, Naunehal S. Matharu, Natalie Landeck, Kelvin Luk, Ronald Melki, Philipp J. Kahle, Simone Hornemann, Tuomas P. J. Knowles, Mark R. Cookson, Magdalini Polymenidou, Mathias Jucker, Adriano Aguzzi
Summary: The expression pattern of LAG3 in human and mouse brains was analyzed, with no evidence of neurons expressing LAG3. While LAG3 was confirmed to interact with alpha-synuclein fibrils, the specificity of this interaction appears limited. Additionally, overexpression of LAG3 did not worsen alpha-synuclein pathology.
EMBO MOLECULAR MEDICINE
(2021)
Article
Neurosciences
Savannah M. Rocha, Collin M. Bantle, Tawfik Aboellail, Debotri Chatterjee, Richard J. Smeyne, Ronald B. Tjalkens
Summary: This study establishes a reproducible murine model of rotenone-induced Parkinson's disease and explores the effects of rotenone exposure on neuroinflammation, protein aggregation, and loss of dopaminergic neurons. The results indicate that rotenone exposure leads to progressive accumulation and regional spread of p129 aggregates, which precede the maximal loss of dopaminergic neurons. The activation of glial cells and aggregation of p129 appear to be driving factors in neurodegeneration following rotenone-induced neurotoxic stress.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Chemistry, Analytical
Yu P. Zhang, Evgeniia Lobanova, Derya Emin, Sergey V. Lobanov, Antonina Kouli, Caroline H. Williams-Gray, David Klenerman
Summary: This study introduces a new method for the diagnosis of early Parkinson's disease. The results show that the proportion of soluble alpha-synuclein aggregates can distinguish between Parkinson's disease patients and control groups, with Parkinson's disease patients having a higher proportion of larger and rounder alpha-synuclein aggregates. By combining the number and morphology of the aggregates, a new biomarker with improved accuracy for early Parkinson's disease diagnosis was constructed.
ANALYTICAL CHEMISTRY
(2023)
Article
Clinical Neurology
Cheng Jiang, Franziska Hopfner, Daniela Berg, Michele T. Hu, Andrea Pilotto, Barbara Borroni, Jason J. Davis, George K. Tofaris
Summary: The study demonstrates that measuring alpha-synuclein levels above 14 pg/mL in L1CAM-immunocaptured serum exosomes can robustly differentiate Parkinson's disease from other movement disorders. Furthermore, elevated levels of exosomal clusterin in individuals with 4-repeat tauopathies, combined with alpha-synuclein, improves the assay's performance in distinguishing Parkinson's disease from 4-repeat tauopathies. However, correction for the generic exosomal protein syntenin-1 did not consistently enhance the assay's performance.
MOVEMENT DISORDERS
(2021)
Article
Medicine, Research & Experimental
George K. Tofaris, Michel Goedert, Maria Grazia Spillantini
COLD SPRING HARBOR PERSPECTIVES IN MEDICINE
(2017)
Article
Clinical Neurology
Mindaugas Jonikas, Martin Madill, Alexandre Mathy, Theresa Zekoll, Christos E. Zois, Simon Wigfield, Marzena Kurzawa-Akanbi, Cathy Browne, David Sims, Patrick F. Chinnery, Sally A. Cowley, George K. Tofaris
ANNALS OF NEUROLOGY
(2018)
Review
Clinical Neurology
George K. Tofaris, Noel J. Buckley
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2018)
Review
Biochemistry & Molecular Biology
Leonidas Stefanis, Evangelia Emmanouilidou, Marina Pantazopoulou, Deniz Kirik, Kostas Vekrellis, George K. Tofaris
JOURNAL OF NEUROCHEMISTRY
(2019)
Article
Clinical Neurology
Cheng Jiang, Franziska Hopfner, Antigoni Katsikoudi, Robert Hein, Candan Catli, Samuel Evetts, Yongzhi Huang, Hong Wang, John W. Ryder, Gregor Kuhlenbaumer, Guenther Deuschl, Alessandro Padovani, Daniela Berg, Barbara Borroni, Michele T. Hu, Jason J. Davis, George K. Tofaris
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2020)
Article
Chemistry, Analytical
Ying Fu, Cheng Jiang, George K. Tofaris, Jason J. Davis
ANALYTICAL CHEMISTRY
(2020)
Article
Multidisciplinary Sciences
Benedict Tanudjojo, Samiha S. Shaikh, Alexis Fenyi, Luc Bousset, Devika Agarwal, Jade Marsh, Christos Zois, Sabrina Heman-Ackah, Roman Fischer, David Sims, Ronald Melki, George K. Tofaris
Summary: Alpha-synuclein plays a critical role in the pathogenesis of Parkinson's disease and related disorders, causing degeneration of human dopaminergic neurons. The toxicity of alpha-synuclein strains depends on aggregate burden, determined by monomer levels and conformation, and influenced by differential interactomes. Parkinson's disease-associated genes influence the phenotypic manifestation of strains in human neurons.
NATURE COMMUNICATIONS
(2021)
Review
Nanoscience & Nanotechnology
Cheng Jiang, Ying Fu, Guozhen Liu, Bowen Shu, Jason Davis, George K. Tofaris
Summary: Extracellular vesicles (EVs) play a crucial role in molecular trafficking, intercellular transport, and protein egress. They can be detected in bodily fluids and offer opportunities for biomarker discovery. Multiplexing platforms can achieve breakthroughs in analytical power, throughput, and consistency.
NANO-MICRO LETTERS
(2022)
Review
Biochemistry & Molecular Biology
George K. Tofaris
Summary: alpha-Synuclein aggregation is a critical molecular process in Parkinson's disease pathogenesis, and its nature influences the clinical heterogeneity. Alpha-synuclein assemblies need to exhibit seeding competency and toxicity for neurodegeneration to occur. It is currently unknown which alpha-synuclein assemblies are most relevant to the human condition.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Clinical Neurology
Aikaterini Vezyroglou, Rhoda Akilapa, Katy Barwick, Saskia Koene, Catherine A. Brownstein, Muriel Holder-Espinasse, Andrew E. Fry, Andrea H. Nemeth, George K. Tofaris, Eleanor Hay, Imelda Hughes, Sahar Mansour, Santosh R. Mordekar, Miranda Splitt, Peter D. Turnpenny, Demetria Demetriou, Tamara T. Koopmann, Claudia A. L. Ruivenkamp, Pankaj B. Agrawal, Lucinda Carr, Virginia Clowes, Neeti Ghali, Susan Elizabeth Holder, Jessica Radley, Alison Male, Sanjay M. Sisodiya, Manju A. Kurian, J. Helen Cross, Meena Balasubramanian
Summary: This study described the clinical features of individuals carrying ATP1A3 variants and reviewed all published ATP1A3 variants associated with human neurologic disease to demonstrate the heterogeneous clinical spectrum of the gene and identify phenotypic overlap between patients, streamlining the diagnostic process.
Article
Genetics & Heredity
Joohyun Park, Arianna Tucci, Valentina Cipriani, German Demidov, Clarissa Rocca, Jan Senderek, Michaela Butryn, Ana Velic, Tanya Lam, Evangelia Galanaki, Elisa Cali, Letizia Vestito, Reza Maroofian, Natalie Deininger, Maren Rautenberg, Jakob Admard, Gesa-Astrid Hahn, Claudius Bartels, Nienke J. H. van Os, Rita Horvath, Patrick F. Chinnery, May Yung Tiet, Channa Hewamadduma, Marios Hadjivassiliou, George K. Tofaris, Nicholas W. Wood, Stefanie N. Hayer, Friedemann Bender, Benita Menden, Isabell Cordts, Katrin Klein, Huu Phuc Nguyen, Joachim K. Krauss, Christian Blahak, Tim M. Strom, Marc Sturm, Bart van de Warrenburg, Holger Lerche, Boris Macek, Matthis Synofzik, Stephan Ossowski, Dagmar Timmann, Marc E. Wolf, Damian Smedley, Olaf Riess, Ludger Schoels, Henry Houlden, Tobias B. Haack, Holger Hengel
Summary: This study investigated heterozygous variants in the UCHL1 gene and identified a novel disease mechanism associated with ataxia. Through gene-burden analyses and proteomics, it was found that haploinsufficiency of UCHL1 can cause neurodegenerative disorders.
GENETICS IN MEDICINE
(2022)
Article
Chemistry, Analytical
Mohamed Sharafeldin, Shijun Yan, Cheng Jiang, George K. Tofaris, Jason J. Davis
Summary: We present a scalable, fast, and low-cost method for extracting cargo proteins from exosome subpopulations using an alternating (AC) magnetic field to facilitate the mixing of antibody-coated magnetic beads (MBs) with serum samples. By applying this method, we were able to achieve high capture efficiencies of >70% from <50 μL of neat serum in just 30 minutes. This approach, when combined with array-based assaying and a standard duplex electrochemical sandwich ELISA, enabled the detection of sub pg/mL levels of α-synuclein content with excellent precision and a sample-to-answer time of approximately 75 minutes. The high performance and semi-automation of this method hold promise for low-cost Parkinson's disease diagnostics and exosomal biomarker analyses.
ANALYTICAL CHEMISTRY
(2023)
Article
Clinical Neurology
Jussi Pekka Tolonen, Ricardo Parolin Schnekenberg, Simon Mcgowan, David Sims, Meriel Mcentagart, Frances Elmslie, Debbie Shears, Helen Stewart, George K. Tofaris, Tabib Dabir, Patrick J. Morrison, Diana Johnson, Marios Hadjivassiliou, Sian Ellard, Charles Shaw-Smith, Anna Znaczko, Abhijit Dixit, Mohnish Suri, Ajoy Sarkar, Rachel E. Harrison, Gabriela Jones, Henry Houlden, Giorgia Ceravolo, Joanna Jarvis, Jonathan Williams, Morag E. Shanks, Penny Clouston, Julia Rankin, Lubov Blumkin, Tally Lerman-Sagie, Penina Ponger, Salmo Raskin, Katariina Granath, Johanna Uusimaa, Hector Conti, Emma Mccann, Shelagh Joss, Alexander J. M. Blakes, Kay Metcalfe, Helen Kingston, Marta Bertoli, Rachel Kneen, Sally Ann Lynch, Inmaculada Martinez Albaladejo, Austen Peter Moore, Wendy D. Jones, Esther B. E. Becker, Andrea H. Nemeth
Summary: The ITPR1 gene encodes the IP3 receptor type 1, which plays a critical role in cerebellar calcium signaling. Pathogenic missense variants in ITPR1 cause various diseases, including SCA29 and GLSP. This study aimed to identify new cases, describe the spectrum of missense variants, and investigate disease progression.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Marta F. Pereira, Tim Buchanan, Guenter U. Hoeglinger, Marko Bogdanovic, George Tofaris, Simon Prangnell, Nagaraja Sarangmat, James J. FitzGerald, Chrystalina A. Antoniades
Summary: This study investigated the longitudinal changes in symptoms of progressive supranuclear palsy (PSP) over a period of 2 years. The findings suggest that clinical rating scales are more effective in detecting motor decline than cognitive decline in PSP. Multiple follow-up time points should be included in longitudinal studies of PSP to accurately capture the progression of the disease.
BMJ NEUROLOGY OPEN
(2022)
Article
Chemistry, Analytical
Qian Li, George K. Tofaris, Jason J. Davis
ANALYTICAL CHEMISTRY
(2017)
