Article
Clinical Neurology
Sitki Cem Parlar, Francis P. P. Grenn, Jonggeol Jeffrey Kim, Cornelis Baluwendraat, Ziv Gan-Or
Summary: This review aims to generate and share a comprehensive database for GBA1 variants reported in Parkinson's disease (PD) to support future research and clinical trials. A total of 371 GBA1 variants in PD were found and a browser containing up-to-date information on these variants was created. The classification and browser presented in this work will inform and support basic, translational, and clinical research on GBA1-PD.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Marco Toffoli, Abigail Higgins, Chiao Lee, Sofia Koletsi, Xiao Chen, Michael Eberle, Fritz J. Sedlazeck, Stephen Mullin, Christos Proukakis, Anthony H. Schapira
Summary: Through studying a large cohort, we found that GBA haplotypes do not affect age at diagnosis of PD.
MOVEMENT DISORDERS
(2021)
Article
Biotechnology & Applied Microbiology
Carolin Gabbert, Susen Schaake, Theresa Lueth, Christoph Much, Christine Klein, Jan O. Aasly, Matthew J. Farrer, Joanne Trinh
Summary: This study utilized Oxford Nanopore sequencing to determine the frequency and pathogenicity of GBA1 variants in Norwegian Parkinson's disease patients and controls. The findings showed that the NGMLR/Minimap2-BCFtools pipeline had the highest accuracy for variant calls. Thirteen rare GBA1 variants were identified, with two predicted to be (likely) pathogenic. Parkinson's disease patients were found to have a 4.11 times higher odds of carrying the common GBA1 variants compared to controls.
Article
Multidisciplinary Sciences
Kelly E. Glajch, Tim E. Moors, Yi Chen, Pascal A. Bechade, Alice Y. Nam, Molly M. Rajsombath, Thomas D. McCaffery, Ulf Dettmer, Andreas Weihofen, Warren D. Hirst, Dennis J. Selkoe, Silke Nuber
Summary: Loss-of-function mutations in GBA1 are strong genetic risk factors for Lewy body disorders, enhancing GCase activity can improve αS dyshomeostasis and reduce lipid-rich aggregates, ameliorating PD-like phenotypes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Clinical Neurology
Nir Giladi, Roy N. Alcalay, Gary Cutter, Thomas Gasser, Tanya Gurevich, Guenter U. Hoeglinger, Kenneth Marek, Claudio Pacchetti, Anthony H. Schapira, Clemens R. Scherzer, Tanya Simuni, Pascal Minini, S. Pablo Sardi, M. Judith Peterschmitt
Summary: The safety, efficacy, and target engagement of venglustat in early-stage Parkinson's disease patients with GBA1 variants were assessed. The study showed that venglustat had a satisfactory safety profile but did not show beneficial treatment effect compared with placebo. These findings suggest that glucosylceramide synthase inhibition with venglustat may not be a viable therapeutic approach for GBA1-associated Parkinson's disease.
Article
Clinical Neurology
Carlo Alberto Artusi, Leonardo Lopiano
Summary: Parkinson's disease (PD) patients with glucosylceramidase beta 1 (GBA1) gene mutations often have an earlier onset and more aggressive disease course, with increased neuropsychological issues. Deep brain stimulation (DBS) is a common therapeutic option for PD patients with disabling motor fluctuations and no dementia, showing good outcomes in terms of daily living activities and quality of life improvement. However, studies suggest that PD patients with GBA1 variants may have a worse DBS outcome due to accelerated cognitive decline. This summary highlights the current literature, identifies knowledge gaps, and proposes suggestions for further research and clinical practice in using DBS for PD patients with GBA1 variants.
FRONTIERS IN NEUROLOGY
(2023)
Review
Biotechnology & Applied Microbiology
M. Sahyadri, Abhishek P. R. Nadiga, Seema Mehdi, K. Mruthunjaya, Pawan G. Nayak, Vipan K. Parihar, S. N. Manjula
Summary: Mitochondria and lysosomes play important roles in maintaining cellular homeostasis, and the connections between them may be associated with Parkinson's disease. Mutations in GBA1 have been found in the neurons of PD patients, leading to abnormal mitochondria-lysosome connections, and the use of GCase modulators may help restore normal function.
Article
Clinical Neurology
Jingru Ren, Ronggui Zhang, Chenxi Pan, Jianxia Xu, Haochen Sun, Ping Hua, Li Zhang, Wenbin Zhang, Pingyi Xu, Changyan Ma, Weiguo Liu
Summary: This study aimed to determine the frequency of GBA-related PD and the relationship between GBA variant severity and clinical characteristics in a large Chinese cohort. The results showed that GBA-PD is highly prevalent in the Chinese population, and patients carrying severe and complex variants have more severe symptoms.
EUROPEAN JOURNAL OF NEUROLOGY
(2022)
Article
Clinical Neurology
Sweta Ghatti, Esther Yoon, Grisel Lopez, Debra Ehrlich, Silvina G. Horovitz
Summary: This study investigated the relationship between GBA1 gene mutations and cortical thickness in PD patients. The results showed that PD patients had thinner cortex in the parietal and postcentral regions, regardless of the genotype. Particularly, patients with N370S variants had significantly higher levels of neurofilament light in the serum.
JOURNAL OF NEUROLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jenny Do, Gani Perez, Bahafta Berhe, Nahid Tayebi, Ellen Sidransky
Summary: This study investigated the behavioral phenotype of gba(+)(/-)//SNCA(A53T) mice, finding that these mice showed more olfactory and motor deficits compared to wildtype mice at 15 months of age. However, differences between gba(+)(/-)//SNCA(A53T) and SNCA(A53T) mice were generally not statistically significant, possibly due to small sample sizes. Furthermore, the study suggested that while gba haploinsufficiency leads to a more rapid demise, it may not necessarily result in an earlier prodromal stage due to other contributing factors such as aging, oxidative stress, and epigenetics.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Clinical Neurology
Cameron Miller-Patterson, Jesse Y. Hsu, Allison W. Willis, Ali G. Hamedani
Summary: This study aimed to evaluate whether functional limitations exist in individuals with Parkinson disease before diagnosis. Using Medicare-linked data from the National Health and Aging Trends Study (NHATS) in the US, researchers found that individuals with prodromal Parkinson disease may have greater impairment in mobility and strength up to 3 years prior to diagnosis compared with the general population.
Article
Multidisciplinary Sciences
Xiangli Zhao, Yi Lin, Benjamin Liou, Wenyu Fu, Jinlong Jian, Venette Fannin, Wujuan Zhang, Kenneth D. R. Setchell, Gregory A. Grabowski, Ying Sun, Chuan-ju Liu
Summary: PGRN plays a crucial role in the pathologies associated with GBA1/Gba1 mutations, as demonstrated by in vivo and ex vivo evidence in this study. Additionally, a PGRN-derived biologic that can penetrate the blood-brain barrier has been developed for the treatment of nGD and PD.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Clinical Neurology
R. Balestrino, T. Martone, M. Toffoli, E. Montanaro, M. Fabbri, C. A. Artusi, A. Romagnolo, M. Zibetti, M. Rizzone, S. Goldwurm, L. Lopiano, A. H. V. Schapira
Summary: This study analyzed the genetic mutations of 56 LCIG patients and retrospectively analyzed their motor and neuropsychological outcomes. The results showed no significant differences in motor or neuropsychological outcomes between patients with and without gene mutations/variants. PD patients with GBA mutations responded well to LCIG treatment in terms of motor symptoms.
NEUROLOGICAL SCIENCES
(2023)
Article
Clinical Neurology
Eileen E. Moran, Susan B. Bressman, Roberto A. Ortega, Deborah Raymond, William C. Nichols, Christina A. Palmese, Sonya Elango, Matthew Swan, Vicki Shanker, Imali Perera, Cuiling Wang, Molly E. Zimmerman, Rachel Saunders-Pullman
Summary: Mutations and variants in the glucocerebrosidase (GBA) gene are common genetic risk factors for Parkinson's disease (PD), but carriers without PD show poorer performance in executive functioning while no significant differences are observed in other domains. This suggests that most GBA mutation carriers may not present pre-manifest non-motor or motor features associated with PD.
FRONTIERS IN NEUROLOGY
(2021)
Review
Pharmacology & Pharmacy
Elisa Menozzi, Marco Toffoli, Anthony H. V. Schapira
Summary: The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. Biallelic variants in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder characterized by loss of GCase activity and aberrant intracellular accumulation of GCase substrates. Carriers of GBA1 variants have an increased risk of developing Parkinson disease (PD), with odds ratio ranging from 2.2 to 30 according to variant severity. GBA1 variants which do not cause GD in homozygosis can also increase PD risk.
PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Clinical Neurology
J. Talbot, R. Stuckey, L. Crawford, S. Weatherby, S. Mullin
Summary: This study presented the outcomes of erenumab treatment in chronic migraine patients who had previously shown unsatisfactory response to onabotulinumtoxinA. The results showed significant improvements in pain, medication use, and quality of life over the 9-month treatment period.
JOURNAL OF HEADACHE AND PAIN
(2021)
Article
Clinical Neurology
Stephen Mullin, Morten Gersel Stokholm, Derralyn Hughes, Atul Mehta, Peter Parbo, Rainer Hinz, Nicola Pavese, David J. Brooks, Anthony H. Schapira
Summary: The study found that carriers of glucocerebrosidase gene mutations without Parkinson's disease also present neuroinflammation. Microglial activation was observed in brain regions susceptible to Lewy pathology. Importantly, the degree of hyposmia was positively correlated with nigral binding potential.
MOVEMENT DISORDERS
(2021)
Article
Clinical Neurology
Marco Toffoli, Abigail Higgins, Chiao Lee, Sofia Koletsi, Xiao Chen, Michael Eberle, Fritz J. Sedlazeck, Stephen Mullin, Christos Proukakis, Anthony H. Schapira
Summary: Through studying a large cohort, we found that GBA haplotypes do not affect age at diagnosis of PD.
MOVEMENT DISORDERS
(2021)
Review
Genetics & Heredity
Jacob Oliver Day, Stephen Mullin
Summary: The genetic landscape of Parkinson's disease includes rare high penetrance pathogenic variants, genetic risk factor variants, and high frequency, low penetrance variants which contribute to the risk of developing the disease. Understanding these influences can have a major impact on the clinical care of PD patients.
Article
Clinical Neurology
Abigail Louise Higgins, Marco Toffoli, Stephen Mullin, Chiao-Yin Lee, Sofia Koletsi, Micol Avenali, Fabio Blandini, Anthony H. Schapira
Summary: Mutations in the GBA gene can cause Gaucher disease and are the most common genetic risk factor for Parkinson's disease. Diagnosis of Parkinson's disease relies on motor features, but prodromal symptoms may allow for earlier prediction of the disease. The RAPSODI GD study aims to assess a large cohort of GBA mutation carriers to aid in earlier diagnosis of Parkinson's disease.
NEURODEGENERATIVE DISEASE MANAGEMENT
(2021)
Meeting Abstract
Clinical Neurology
Megan Courtman, Mark Thurston, Lucy McGavin, Camille Caroll, Lingfen Sun, Emmanuel Ifeachor, Stephen Mullin
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Article
Biology
Marco Toffoli, Xiao Chen, Fritz J. Sedlazeck, Chiao-Yin Lee, Stephen Mullin, Abigail Higgins, Sofia Koletsi, Monica Emili Garcia-Segura, Esther Sammler, Sonja W. Scholz, Anthony H. V. Schapira, Michael A. Eberle, Christos Proukakis
Summary: This study introduces two methods for resolving GBA variants and shows that Gauchian outperforms other methods in GBA analysis. Applying Gauchian to sequencing data of over 10,000 individuals reveals that copy number variants (CNVs) spanning GBAP1 are relatively common in Africans, and CNV frequencies in PD and LBD patients are similar to controls. Additionally, Gauchian detects more GBA variants in LBD than PD, especially severe ones. These findings highlight the importance of accurate GBA analysis in these patients.
COMMUNICATIONS BIOLOGY
(2022)
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
Psychiatry
James M. Clay, Kiera A. Baker, Roxana D. Mezabrovschi, Giacomo Berti, Grant S. Shields, George M. Slavich, Lorenzo D. Stafford, Matthew O. Parker
Summary: Stress, trait impulsivity, and emotional dysregulation independently predict alcohol use and misuse. This study explores the potential mechanisms linking these risk factors and finds that emotional dysregulation fully mediates the relationship between cumulative lifetime stressor exposure and lifetime alcohol use. The study also reveals that different facets of impulsivity moderate these associations, suggesting a complex interplay between these factors.
JOURNAL OF PSYCHIATRIC RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Victoria Meslier, Elisa Menozzi, Aymeric David, Christian Morabito, Sara Lucas Del Pozo, Alexandre Famechon, Janet North, Benoit Quinquis, Sofia Koletsi, Jane Macnaughtan, Roxana Mezabrovschi, S. Dusko Ehrlich, Anthony H. V. Schapira, Mathieu Almeida
Summary: Recent attention has highlighted the importance of oral microbiota in human health and disease, especially in Parkinson's disease. It has been found that a semi-automated DNA extraction protocol can improve sample processing efficiency without compromising the structure of the oral microbiome.
Article
Neurosciences
Nihal A. Salem, Lawrence Manzano, Michael W. Keist, Olga Ponomareva, Amanda J. Roberts, Marisa Roberto, R. Dayne Mayfield
Summary: This study identified cell-type specific gene expression changes associated with alcohol dependence in the medial prefrontal cortex of mice. The results revealed dysregulated gene co-expression networks and differentially expressed genes in multiple cell types, highlighting the involvement of inhibitory neurons and astrocytes in alcohol dependence. Novel targets for studying molecular mechanisms contributing to alcohol dependence were also identified.
NEUROBIOLOGY OF DISEASE
(2024)
Article
Neurosciences
Laura E. Hawley, Megan Stringer, Abigail J. Deal, Andrew Folz, Charles R. Goodlett, Randall J. Roper
Summary: This study found that the overexpression of DYRK1A protein in Down syndrome mice varies with age, sex, and brain region, and reducing the copy number of Dyrk1a can decrease the expression of DYRK1A. These sex-specific patterns of DYRK1A overexpression may provide mechanistic targets for therapeutic intervention in Down syndrome.
NEUROBIOLOGY OF DISEASE
(2024)