Review
Clinical Neurology
Mattia Volta
Summary: The discovery of mutations in LRRK2 and GBA1 that are linked to Parkinson's disease provides further evidence of the involvement of autophagy and lysosomal pathways in the disease's pathology. The development of genetic rodent models for LRRK2 and GBA1 has the potential to enhance our understanding of lysosome alterations in Parkinson's disease and provide new insights. Further research is needed to exploit these rodent models in the fight against the disease.
Review
Clinical Neurology
Mattia Volta
Summary: The discovery of mutations in LRRK2 and GBA1 has provided evidence for the involvement of autophagy and lysosome pathways in Parkinson's disease. These mutations slow down the degradation of alpha-synuclein, leading to dysfunction in the neuropathology of the disease. The development of genetic rodent models holds promise for studying pathogenic processes and validating drugs.
Review
Biochemistry & Molecular Biology
Jasmin Galper, Woojin S. Kim, Nicolas Dzamko
Summary: Genetic alterations in the LRRK2 gene are a common risk factor for Parkinson's disease. LRRK2 alterations are associated with changes in lipid pathways, which can lead to cellular pathology.
Article
Clinical Neurology
Jonas M. den Heijer, Valerie C. Cullen, Diana R. Pereira, Yalcin Yavuz, Marieke L. de Kam, Hendrika W. Grievink, Matthijs Moerland, Nancy Leymarie, Kshitij Khatri, Imelda Sollomoni, Leslie Spitalny, Lindsay Dungeon, Dana C. Hilt, Craig Justman, Peter Lansbury, Geert Jan Groeneveld
Summary: This study assessed the variability of various glycosphingolipids (GSLs) in plasma, peripheral blood mononuclear cells (PBMCs), and cerebrospinal fluid (CSF) across GBA-PD, iPD, and HVs. The results showed that plasma levels of glucosylceramide were slightly higher in GBA-PD compared with iPD and HVs, while intracellular levels were comparable. There was no correlation between GSLs in different matrices.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Jonas M. den Heijer, Valerie C. Cullen, Diana R. Pereira, Yalcin Yavuz, Marieke L. de Kam, Hendrika W. Grievink, Matthijs Moerland, Nancy Leymarie, Kshitij Khatri, Imelda Sollomoni, Leslie Spitalny, Lindsay Dungeon, Dana C. Hilt, Craig Justman, Peter Lansbury, Geert Jan Groeneveld
Summary: This study assessed the variability of various GSLs in plasma, PBMCs, and CSF across GBA-PD, iPD, and HVs. Glucosylceramide was found to be a stable biomarker for GBA-PD clinical trials, while lactosylceramide and glucosylsphingosine were affected by leukocyte subtypes in PBMCs. GBA-PD could be differentiated from iPD and HVs based on glucosylceramide levels in plasma.
MOVEMENT DISORDERS
(2023)
Article
Neurosciences
Bruno Lopes Santos-Lobato, Artur F. Schumacher-Schuh, Ignacio F. Mata
Summary: This study aimed to explore the prevalence and odds ratio of specific GBA1 variants in Parkinson's disease patients in Latin America. However, there is a lack of full sequencing GBA1 studies in Latin America.
NPJ PARKINSONS DISEASE
(2022)
Article
Clinical Neurology
Gian D. Pal, Daniel M. Corcos, Leo Verhagen Metman, Zvi Israel, Hagai Bergman, David Arkadir
Summary: Genetic subtyping of patients with Parkinson's disease may help predict the cognitive and motor outcomes of subthalamic deep brain stimulation. However, there are still controversies and gaps in understanding the effects of STN-DBS on PD patients with pathogenic variants in the GBA1 gene. Further research is needed to determine the clinical significance, risk-to-benefit ratio, and strategies to minimize the negative effects of STN-DBS. Genetic testing for GBA1 may be considered in PD patients considering DBS to properly assess the potential risks and benefits.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Matthew Surface, Manisha Balwani, Cheryl Waters, Alexander Haimovich, Ziv Gan-Or, Karen S. Marder, Tammy Hsieh, Linxia Song, Shalini Padmanabhan, Frank Hsieh, Kalpana M. Merchant, Roy N. Alcalay
Summary: This study found significantly higher levels of plasma glucosylsphingosine in GBA1 N370S carriers, independent of disease status. This opens up the potential for future assessment of glucosylsphingosine as a clinically meaningful biomarker of GBA1-PD.
MOVEMENT DISORDERS
(2022)
Article
Cell Biology
Electra Brunialti, Alessandro Villa, Marco Toffoli, Sara Lucas Del Pozo, Nicoletta Rizzi, Clara Meda, Adriana Maggi, Anthony H. V. Schapira, Paolo Ciana
Summary: Microglia are heterogenous cells in the nervous system that have distinct populations contributing to specific processes, including neuroprotection. Our study found that male microglia tend to have a more pro-inflammatory phenotype, while female microglia are more sensitive to glucocerebrosidase inhibition. Furthermore, glucocerebrosidase inhibition impaired the ability of female microglia to enhance the Nrf2-dependent detoxification pathway in neurons.
Article
Geriatrics & Gerontology
Yuri L. Sosero, Eric Yu, Lynne Krohn, Uladzislau Rudakou, Kheireddin Mufti, Jennifer A. Ruskey, Farnaz Asayesh, Sandra B. Laurent, Dan Spiegelman, Stanley Fahn, Cheryl Waters, S. Pablo Sardi, Sara Bandres-Ciga, Roy N. Alcalay, Ziv Gan-Or, Konstantin Senkevich
Summary: The study found that the LRRK2 p.M1646T variant is associated with an increased risk of PD and elevated GCase activity in peripheral blood. However, the effect of this variant on PD risk is relatively small.
NEUROBIOLOGY OF AGING
(2021)
Article
Neurosciences
Sinthuja Pachchek, Zied Landoulsi, Lukas Pavelka, Claudia Schulte, Elena Buena-Atienza, Caspar Gross, Ann-Kathrin Hauser, Dheeraj Reddy Bobbili, Nicolas Casadei, Patrick May, Rejko Krueger, Geeta Acharya, Gloria Aguayo, Myriam Alexandre, Muhammad Ali, Wim Ammerlann, Giuseppe Arena, Rudi Balling, Michele Bassis, Roxane Batutu, Katy Beaumont, Regina Becker, Camille Bellora, Guy Berchem, Daniela Berg, Alexandre Bisdorff, Ibrahim Boussaad, David Bouvier, Kathrin Brockmann, Jessica Calmes, Lorieza Castillo, Gessica Contesotto, Nancy De Bremaeker, Nico Diederich, Rene Dondelinger, Nancy E. Ramia, Daniela Esteves, Guy Fagherazzi, Jean-Yves Ferrand, Katrin Frauenknecht, Manon Gantenbein, Thomas Gasser, Piotr Gawron, Soumyabrata Ghosh, Marijus Giraitis, Enrico Glaab, Martine Goergen, Elisa Gomez De Lope, Jerome Graas, Mariella Graziano, Valentin Groues, Anne Gruenewald, Wei Gu, Gael Hammot, Anne-Marie Hanff, Linda Hansen, Michael Heneka, Estelle Henry, Sylvia Herbrink, Sascha Herzinger, Michael Heymann, Michele Hu, Alexander Hundt, Nadine Jacoby, Jacek Jaroslaw Lebioda, Yohan Jarosz, Sonja Jonsdottir, Quentin Klopfenstein, Jochen Klucken, Pauline Lambert, Roseline Lentz, Inga Liepelt, Robert Liszka, Laura Longhino, Victoria Lorentz, Paula Cristina Lupu, Taina M. Marques, Clare Mackay, Walter Maetzler, Katrin Marcus, Guilherme Marques, Patricia Martins Conde, Deborah Mcintyre, Chouaib Mediouni, Francoise Meisch, Myriam Menster, Maura Minelli, Michel Mittelbronn, Brit Mollenhauer, Friedrich Muehlschlegel, Romain Nati, Ulf Nehrbass, Sarah Nickels, Beatrice Nicolai, Jean-Paul Nicolay, Fozia Noor, Marek Ostaszewski, Clarissa P. C. Gomes, Claire Pauly, Laure Pauly, Magali Perquin, Rosalina Ramos Lima, Armin Rauschenberger, Rajesh Rawal, Kirsten Roomp, Eduardo Rosales, Isabel Rosety, Estelle Sandt, Stefano Sapienza, Venkata Satagopam, Margaux Schmitt, Sabine Schmitz, Reinhard Schneider, Jens Schwamborn, Raquel Severino, Amir Sharify, Ekaterina Soboleva, Kate Sokolowska, Hermann Thien, Elodie Thiry, Rebecca Ting Jiin Loo, Christophe Trefois, Johanna Trouet, Olena Tsurkalenko, Michel Vaillant, Mesele Valenti, Gilles Van Cutsem, Carlos Vega, Liliana Vilas Boas, Maharshi Vyas, Richard Wade-Martins, Paul Wilmes, Evi Wollscheid-Lengeling, Gelani Zelimkhanov
Summary: Heterozygous variants in the GBA1 gene are recognized as a risk factor for Parkinson's disease. A study in Luxembourg using long-read DNA sequencing technology revealed a high prevalence of GBA1 variants as the major genetic risk for PD, providing an important advancement in accurate variant calling and access to treatment options for GBA1 carriers.
NPJ PARKINSONS DISEASE
(2023)
Article
Clinical Neurology
Grisel J. Lopez, Jens Lichtenberg, Nahid Tayebi, Emory Ryan, Abigail L. Lecker, Ellen Sidransky
Summary: Carrying GBA1 mutations, whether or not Parkinson's disease is present, leads to a significant decline or loss of olfactory function. The majority of individuals without Parkinson's disease maintain stable olfactory function over time. A small subgroup of mutation carriers exhibits moderate to severe olfactory dysfunction.
FRONTIERS IN NEUROLOGY
(2022)
Review
Genetics & Heredity
Eun-Mi Hur, Byoung Dae Lee
Summary: Parkinson's disease is a heterogeneous neurodegenerative disease characterized by the loss of dopaminergic neurons and the formation of proteinaceous inclusions. Aging is considered a major risk factor influencing the progression of PD, with common changes in cellular functions shared by aging and PD. Mutations in the LRRK2 gene are a common genetic cause of both familial and sporadic PD, and may interact with aging to contribute to PD pathologies.
Review
Clinical Neurology
Elisa Menozzi, Anthony H. V. Schapira, Fabio Blandini, Micol Avenali
Summary: The purpose of this review is to identify sensitive markers that can stratify the risk of Parkinson's disease (PD) in non-manifesting carriers of GBA1 and LRRK2 variants. Studies have shown that while the penetrance of PD is similar in GBA1 and LRRK2 variant carriers (10 - 30%), these individuals have distinct preclinical profiles. GBA1 variant carriers at higher risk of PD may exhibit prodromal symptoms such as hyposmia, increased levels of alpha-synuclein in peripheral blood mononuclear cells, and dopamine transporter abnormalities. LRRK2 variant carriers at higher risk of PD may show subtle motor abnormalities, higher exposure to certain environmental factors (non-steroidal anti-inflammatory drugs), and peripheral inflammatory profile. This information can assist clinicians in personalized screening and counseling, as well as aid researchers in developing predictive markers and disease-modifying treatments.
CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS
(2023)
Article
Multidisciplinary Sciences
Soojin Kim, Yvette C. Wong, Fanding Gao, Dimitri Krainc
Summary: Mitochondria-lysosome contacts play a crucial role in mediating crosstalk between organelles in human neurons, with defects observed in Parkinson's disease patient derived neurons harboring mutant GBA1 due to dysregulation of TBC1D15 caused by decreased GBA1 activity.
NATURE COMMUNICATIONS
(2021)
Article
Clinical Neurology
Celine Galvagnion, Frederik Ravnkilde Marlet, Silvia Cerri, Anthony H. Schapira, Fabio Blandini, Donato A. Di Monte
Summary: This study found that mutations of the glucocerebrosidase 1 (GBA) gene, a prevalent risk factor for Parkinson's disease, led to altered lipid membrane composition in Parkinson fibroblasts. The altered lipid profile featured increased levels of sphingolipids and shorter-chain sphingolipid molecules. The extent of this alteration was correlated with the reduction of fibroblast glucocerebrosidase activity and accelerated alpha-synuclein aggregation. Treatment with a small molecule chaperone, ambroxol, restored the lipid profile and reversed the pro-aggregation effect. These findings suggest that the GBA mutation and consequent loss of enzymatic activity are associated with a distinct membrane lipid profile, which may increase the risk for alpha-synuclein aggregate pathology.
Article
Neurosciences
Matthew E. Gegg, Elisa Menozzi, Anthony H. V. Schapira
Summary: Dysfunction of the endolysosomal system is associated with the pathogenesis of Parkinson's disease (PD), and genetic variants in the GBA gene are a common risk factor. GCase deficiency in neurons and glia may contribute to PD by promoting the accumulation and spread of alpha-synuclein aggregates. Dysregulation of lipids, including sphingolipids, phospholipids, and cholesterol, as well as neuroinflammation and the interaction between GCase and LRRK2 protein, are also implicated in PD pathogenesis.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Medicine, General & Internal
Uwe Bieri, Michael Scharl, Silvan Sigg, Barbara Maria Szczerba, Yasser Morsy, Jan Hendrik Ruschoff, Peter Hans Schraml, Michael Krauthammer, Lukas John Hefermehl, Daniel Eberli, Cedric Poyet
Summary: The human microbiota has been linked to inflammatory and neoplastic diseases. While the gut microbiome has been extensively studied, the urinary microbiome is still relatively new. Investigating the relationship between bladder cancer and the bladder and intestinal microbiome may provide insights into their pathophysiological relationship. It may also lead to the discovery of non-invasive biomarkers for tumor behavior.
Review
Cell Biology
Laura Smith, Anthony H. V. Schapira
Summary: Mutations in the GBA gene are the most important genetic risk factor for Parkinson's disease (PD), leading to protein metabolism abnormalities, lysosomal dysfunction, and lipid metabolism disorders. These mutations can trigger neurodegenerative processes through various mechanisms, including the accumulation of alpha-synuclein, endoplasmic reticulum stress responses, and mitochondrial dysfunction. Understanding these mechanisms can facilitate the development of targeted therapies for GBA-related PD.
Article
Gastroenterology & Hepatology
Marlene Schwarzfischer, Anna Niechcial, Kristina Handler, Yasser Morsy, Marcin Wawrzyniak, Andrea S. Laimbacher, Kirstin Atrott, Roberto Manzini, Katharina Baebler, Larissa Hering, Egle Katkeviciute, Janine Hafliger, Silvia Lang, Maja E. Keller, Jerome Woodtli, Lisa Eisenbeiss, Thomas Kraemer, Elisabeth M. Schraner, Mahesa Wiesendanger, Sebastian Zeissig, Gerhard Rogler, Andreas E. Moor, Michael Scharl, Marianne R. Spalinger
Summary: This study investigates the interaction between the PTPN22 gene variation and food-grade titanium dioxide nanoparticles in the pathogenesis of inflammatory bowel disease (IBD). The results show that the ingestion of titanium dioxide nanoparticles makes mice carrying the PTPN22 variation susceptible to IBD and triggers severe intestinal inflammation. This demonstrates that environmental factors can interact with genetic risk variants and reverse a protective mechanism into a disease-promoting effect.
Article
Biochemistry & Molecular Biology
Laura J. Smith, Magdalena M. Bolsinger, Kai-Yin Chau, Matthew E. Gegg, Anthony H. Schapira
Summary: Sequence variants or mutations in the GBA gene are the most important risk factor for Parkinson's disease. This study characterizes the effects of the E326K variant in human cells and finds that it behaves differently compared to other common GBA mutations. However, lipid imbalance and alpha-synuclein pathology are still observed.
HUMAN MOLECULAR GENETICS
(2023)
Article
Gastroenterology & Hepatology
Joana Torres, Maria Chaparro, Mette Julsgaard, Konstantinos Katsanos, Zuzana Zelinkova, Manasi Agrawal, Sandro Ardizzone, Marjo Campmans-Kuijpers, Gabriele Dragoni, Marc Ferrante, Gionata Fiorino, Emma Flanagan, Catarina Frias Gomes, Ailsa Hart, Charlotte Rose Hedin, Pascal Juillerat, Annemarie Mulders, Par Myrelid, Aoibhlinn O'Toole, Pauline Riviere, Michael Scharl, Christian Philipp Selinger, Elena Sonnenberg, Murat Toruner, Jantien Wieringa, C. Janneke Van der Woude
JOURNAL OF CROHNS & COLITIS
(2023)
Article
Biochemistry & Molecular Biology
Adam R. R. Smith, David M. M. Richards, Katie Lunnon, Anthony H. V. Schapira, Anna Migdalska-Richards
Summary: Parkinson's disease (PD) is a common movement disorder, and mutations in the GBA1 gene are the most common genetic risk factor for PD. PD-GBA1 is distinct from idiopathic PD in terms of age of onset, neuropsychiatric symptoms, and cognitive impairment. This study found differences in DNA methylation levels of the SNCA gene between PD-GBA1 and idiopathic PD, suggesting the existence of different genetic subtypes within PD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Electra Brunialti, Alessandro Villa, Marco Toffoli, Sara Lucas Del Pozo, Nicoletta Rizzi, Clara Meda, Adriana Maggi, Anthony H. V. Schapira, Paolo Ciana
Summary: Microglia are heterogenous cells in the nervous system that have distinct populations contributing to specific processes, including neuroprotection. Our study found that male microglia tend to have a more pro-inflammatory phenotype, while female microglia are more sensitive to glucocerebrosidase inhibition. Furthermore, glucocerebrosidase inhibition impaired the ability of female microglia to enhance the Nrf2-dependent detoxification pathway in neurons.
Article
Clinical Neurology
Tom Foltynie, Sonia Gandhi, Cristina Gonzalez-Robles, Marie-Louise Zeissler, Georgia Mills, Roger Barker, James Carpenter, Anette Schrag, Anthony Schapira, Oliver Bandmann, Stephen Mullin, Joy Duffen, Kevin McFarthing, Jeremy Chataway, Mahesh Parmar, Camille Carroll
Summary: Multi-arm, multi-stage platform designs have improved the efficiency of clinical trials in the field of oncology. Foltynie et al. discuss the challenges and considerations of using this approach to assess potential disease-modifying treatments in progressive neurological conditions such as Parkinson's disease.
Article
Clinical Neurology
Cornelis Blauwendraat, Nahid Tayebi, Elizabeth Geena Woo, Grisel Lopez, Luca Fierro, Marco Toffoli, Naomi Limbachiya, Derralynn Hughes, Vanessa Pitz, Dhairya Patel, Dan Vitale, Mathew J. Koretsky, Dena Hernandez, Raquel Real, Roy N. Alcalay, Mike A. Nalls, Huw R. Morris, Anthony H. V. Schapira, Manisha Balwani, Ellen Sidransky
Summary: This study found that PD patients with GD1 have a higher genetic risk score, suggesting that common risk variants may affect underlying biological pathways.
MOVEMENT DISORDERS
(2023)
Letter
Clinical Neurology
Marco Toffoli, Anthony H. V. Schapira, Christos Proukakis
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Siegfried Karl Wagner, David Romero-Bascones, Mario Cortina-Borja, Dominic J. Williamson, Robbert R. Struyven, Yukun Zhou, Salil Patel, Rimona S. Weil, Chrystalina A. Antoniades, Eric J. Topol, Edward Korot, Paul J. Foster, Konstantinos Balaskas, Unai Ayala, Maitane Barrenechea, Inigo Gabilondo, Anthony H. V. Schapira, Anthony P. Khawaja, Praveen J. Patel, Jugnoo S. Rahi, Alastair K. Denniston, Axel Petzold, Pearse Andrew Keane
Summary: Individuals with Parkinson's disease (PD) exhibit reduced thickness of the inner nuclear layer (INL) and ganglion cell-inner plexiform layer (GCIPL) of the retina. Changes in these layers occurring several years before clinical presentation highlight a potential role for retinal imaging in stratifying PD risk.
Article
Clinical Neurology
Cornelis Blauwendraat, Nahid Tayebi, Elizabeth Geena Woo, Grisel Lopez, Luca Fierro, Marco Toffoli, Naomi Limbachiya, Derralynn Hughes, Vanessa Pitz, Dhairya Patel, Dan Vitale, Mathew J. Koretsky, Dena Hernandez, Raquel Real, Roy N. Alcalay, Mike A. Nalls, Huw R. Morris, Anthony H. V. Schapira, Manisha Balwani, Ellen Sidransky
Summary: This study investigated the contribution of PD risk variants to risk for PD in patients with GD1. The results showed that patients with GD1 who developed PD had a significantly higher PD genetic risk score than those without PD. This suggests that common risk variants may affect underlying biological pathways.
MOVEMENT DISORDERS
(2023)
Meeting Abstract
Clinical Neurology
C. Gonzalez-Robles, D. Byrom, R. Chapman, D. Dexter, S. Duty, R. Ellis-Doyle, E. Jabbari, G. Mills, H. Mortiboys, J. Rudiger, E. Sammler, P. Scurfield, S. Stott, G. Tofaris, L. Wei, A. Wong, M. L. Zeissler, C. Carroll, T. Foltynie, O. Bandmann, A. Schapira
MOVEMENT DISORDERS
(2022)