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
Clinical Neurology
Avner Thaler, Nurit Omer, Nir Giladi, Tanya Gurevich, Anat Bar-Shira, Mali Gana-Weisz, Orly Goldstein, Meir Kestenbaum, Jesse M. Cedarbaum, Avi Orr-Urtreger, Shani Shenhar-Tsarfaty, Anat Mirelman
Summary: The study aimed to evaluate the association between biochemical markers, PD severity, and prodromal PD probability score among carriers of GBA and LRRK2 mutations. The results showed that sub-clinical renal impairment is linked to an increased likelihood of prodromal PD, regardless of genetic status, suggesting a potential role of kidney function in PD pathogenesis.
JOURNAL OF NEUROLOGY
(2021)
Article
Neurosciences
Konstantin Senkevich, Uladzislau Rudakou, Ziv Gan-Or
Summary: Parkinson's disease is a complex disorder that may be a mixture of different diseases, with genes playing an important role in patient classification and drug development. GBA, LRRK2, and PRKN are key genes associated with PD, and targeting these genes could lead to novel therapeutic approaches.
Article
Clinical Neurology
Tatiana Usnich, Eva-Juliane Vollstedt, Nathalie Schell, Volha Skrahina, Xenia Bogdanovic, Hanaa Gaber, Toni M. Foerster, Andreas Heuer, Natalia Koleva-Alazeh, Ilona Csoti, Ayse Nazli Basak, Sibel Ertan, Gencer Genc, Peter Bauer, Katja Lohmann, Anne Gruenewald, Emma L. Schymanski, Joanne Trinh, Susen Schaake, Daniela Berg, Doreen Gruber, Stuart H. Isaacson, Andrea A. Kuehn, Brit Mollenhauer, David J. Pedrosa, Kathrin Reetz, Esther M. Sammler, Enza Maria Valente, Franco Valzania, Jens Volkmann, Simone Zittel, Norbert Brueggemann, Meike Kasten, Arndt Rolfs, Christine Klein
Summary: The LIPAD project aims to systematically assess clinical signs and symptoms in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls, and investigate modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data.
FRONTIERS IN NEUROLOGY
(2021)
Review
Neurosciences
Shirley Yin-Yu Pang, Rachel Cheuk Nam Lo, Philip Wing-Lok Ho, Hui-Fang Liu, Eunice Eun Seo Chang, Chi-Ting Leung, Yasine Malki, Zoe Yuen-Kiu Choi, Wing Yan Wong, Michelle Hiu-Wai Kung, David Boyer Ramsden, Shu-Leong Ho
Summary: Mutations in LRRK2 and GBA are the most common genetic causes of Parkinson's disease, affecting the autophagic-lysosomal pathway. These genes influence each other, leading to autophagic defects, alpha-synuclein accumulation, and worsened clinical symptoms. Inhibitors of LRRK2 kinase and activators of GCase show promise in pre-clinical models, but their efficacy in idiopathic Parkinson's disease remains uncertain.
TRANSLATIONAL NEURODEGENERATION
(2022)
Review
Clinical Neurology
Yuri L. Sosero, Ziv Gan-Or
Summary: LRRK2 variants are associated with both familial and sporadic PD. LRRK2-PD presents with benign clinical features and variable pathology, including inconsistent presence of Lewy bodies and significant Alzheimer's disease pathology. The mechanisms of LRRK2-PD are still unclear, but inflammation, vesicle trafficking, lysosomal homeostasis, and ciliogenesis have been suggested. Understanding the role and function of LRRK2 in PD is important as novel therapies targeting LRRK2 are being developed.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2023)
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)
Article
Clinical Neurology
Shachar Shani, Orly Goldstein, Mali Gana-Weisz, Anat Bar-Shira, Avner Thaler, Tanya Gurevich, Anat Mirelman, Nir Giladi, Roy N. Alcalay, Avi Orr-Urtreger
Summary: Recent studies have found a link between Parkinson's disease (PD) and changes in the innate immune system. This study aimed to determine if genetic variations in innate immune genes are differentially associated with PD in different subgroups, including GBA-PD, LRRK2-PD, and non-carrier PD (NC-PD).
PARKINSONISM & RELATED DISORDERS
(2023)
Article
Neurosciences
Avner Thaler, Nurit Omer, Nir Giladi, Tanya Gurevich, Anat Bar-Shira, Mali Gana-Weisz, Orly Goldstein, Meir Kestenbaum, Julia C. Shirvan, Jesse M. Cedarbaum, Avi Orr-Urtreger, Keren Regev, Shani Shenhar-Tsarfaty, Anat Mirelman
Summary: This study aimed to assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers of these mutations, but no evidence of dysregulated immune response was detected among GBA and LRRK2 PD patients and non-manifesting mutation carriers.
JOURNAL OF PARKINSONS DISEASE
(2021)
Article
Multidisciplinary Sciences
Ranjan K. Singh, Ahmed Soliman, Giambattista Guaitoli, Eliza Stoermer, Felix von Zweydorf, Thomas Dal Maso, Asmaa Oun, Laura Van Rillaer, Sven H. Schmidt, Deep Chatterjee, Joshua A. David, Els Pardon, Thomas U. Schwartz, Stefan Knapp, Eileen J. Kennedy, Jan Steyaert, Friedrich W. Herberg, Arjan Kortholt, Christian Johannes Gloeckner, Wim Versees
Summary: Mutations in the LRRK2 gene are a leading cause of Parkinson's disease, while overactivation of LRRK2 is associated with idiopathic form of the disease. Researchers have identified and characterized nanobodies that can bind to different domains of LRRK2 and inhibit or activate its activity. These nanobodies act through an allosteric inhibitor mechanism and provide potential therapeutic strategies for Parkinson's disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Milena Fais, Antonio Dore, Manuela Galioto, Grazia Galleri, Claudia Crosio, Ciro Iaccarino
Summary: Parkinson's disease is a complex neurodegenerative disorder with causes attributed to both genetic and environmental factors. Lipids play a significant role in the pathological pathways of PD, potentially contributing to neuronal toxicity through protein alterations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Clinical Neurology
Nurit Omer, Nir Giladi, Tanya Gurevich, Anat Bar-Shira, Mali Gana-Weisz, Tal Glinka, Orly Goldstein, Meir Kestenbaum, Jesse M. Cedarbaum, Omar S. Mabrouk, Kyle B. Fraser, Julia C. Shirvan, Avi Orr-Urtreger, Anat Mirelman, Avner Thaler
Summary: This study investigated the association between GCase activity, PD phenotype, and prodromal PD probability in carriers of GBA gene mutations, finding that low GCase activity does not explain the clinical phenotype or risk for prodromal PD in this cohort.
MOVEMENT DISORDERS
(2022)
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
Geriatrics & Gerontology
Gregory M. Pontone, Kelly A. Mills
Summary: Depression and anxiety are common and significantly impact quality of life in Parkinson's disease. Current management strategies need to address both motor and psychiatric symptoms, but there is a lack of randomized controlled trials for pharmacological treatment of anxiety and nonpharmacological interventions have not shown efficacy.
AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY
(2021)
Article
Clinical Neurology
Yuting Tang, Lijian Wei, Zhuohua Wu, Pingyi Xu, Mingshu Mo
Summary: This case report describes a patient with Parkinson's disease (PD) who developed the condition after a hypoxic insult and carries a covariant of GBA and LRRK2 genes. This study sheds light on the interaction between genetic and environmental factors in the development of clinical PD.