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
Christina Andica, Koji Kamagata, Wataru Uchida, Yuya Saito, Kaito Takabayashi, Akifumi Hagiwara, Haruka Takeshige-Amano, Taku Hatano, Nobutaka Hattori, Shigeki Aoki
Summary: This study compared the white matter differences between nonmedicated patients with early-stage GBA-PD and iPD using a novel technique, fixel-based analysis. The results showed that patients with GBA-PD had lower white matter density, while patients with iPD had larger white matter fiber bundles. These findings may be related to neurodegenerative diseases, α-synuclein accumulation, and cognitive and motor impairments.
MOVEMENT DISORDERS
(2023)
Article
Biochemistry & Molecular Biology
Silvia Cerri, Cristina Ghezzi, Gerardo Ongari, Stefania Croce, Micol Avenali, Roberta Zangaglia, Donato A. Di Monte, Enza Maria Valente, Fabio Blandini
Summary: This study found that GCase deficiency promotes the release of EVs, leading to increased levels of phosphorylated alpha-syn inside fibroblasts from PD patients. This suggests that dysregulation of EV trafficking and mishandling of alpha-synuclein may play a role in GBA-associated PD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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
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
Neurosciences
Jussi O. T. Sipila, Laura Kytovuori, Tuomas Rauramaa, Hugo Rauhamaa, Valtteri Kaasinen, Kari Majamaa
Summary: Several heterozygous variants of the GBA1 gene have been linked to increased risk of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1-associated PD is more severe than idiopathic PD, and more severe variants are associated with worse clinical phenotypes. A family with a heterozygous p.Pro454Leu variant in GBA1 is reported, which is associated with a diverse range of severe and rapidly progressive neurodegenerative diseases with Lewy bodies. Pathogenicity prediction algorithms and evolutionary analyses suggest that p.Pro454Leu is deleterious.
NPJ PARKINSONS DISEASE
(2023)
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)
Review
Biochemistry & Molecular Biology
Diptaman Chatterjee, Dimitri Krainc
Summary: Beta-glucocerebrosidase, encoded by GBA1, is the most common risk gene associated with Parkinson's disease (PD) and Lewy Body Dementia. Recent studies have shown dysfunction of glucocerebrosidase in both genetic and sporadic forms of PD and related disorders, indicating a broader role of glucocerebrosidase in neurodegeneration. This review highlights the mechanistic characterization of glucocerebrosidase function, which provides insights for the development of novel therapeutics targeting glucocerebrosidase in PD and related disorders.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Rekha Raghunathan, Kathleen Turajane, Li Chin Wong
Summary: Neurodegenerative diseases such as ALS and PD lack biomarkers for diagnosis and treatment efficacy. Proteomic studies have identified potential biomarker proteins in ALS and PD and explored disease-related post-translational modifications. Comparative analysis of relative and absolute quantitative proteomic approaches and recent technological advancements may help identify suitable biomarkers for early diagnosis and treatment efficacy of these diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Cell Biology
Srinivasa Reddy Bonam, Christine Tranchant, Sylviane Muller
Summary: Cellular quality control systems, particularly autophagy, play a crucial role in cell survival and maintaining homeostasis. Different types of autophagy pathways show varying degrees of selectivity towards substrates. In neurodegenerative diseases, such as Parkinson's disease, autophagy is important and therapeutic strategies targeting autophagy may alter disease progression.
Review
Medicine, General & Internal
Yihang Han, Di Wu, Yanjuan Wang, Jian Xie, Zhijun Zhang
Summary: This review summarizes the characteristics of cutaneous nerve synuclein deposits in PD patients and their correlations with clinical phenotypes and gene mutations. These findings have important implications for the diagnosis and classification of PD and provide a deeper understanding of its pathogenesis.
Review
Pharmacology & Pharmacy
Andras Salamon, Denes Zadori, Laszlo Szpisjak, Peter Klivenyi, Laszlo Vecsei
Summary: These small hereditary subgroups are crucially important in drug development, because the general trend is that clinical trials that treat PD patients as a large group, without any separation, do not meet expectations. As a result, no long term conclusions can currently be drawn regarding the effectiveness of the molecules tested in these phase 1 and 2 studies. Further precise studies are needed in the near future.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2022)
Review
Biochemistry & Molecular Biology
Vidal Yahya, Alessio Di Fonzo, Edoardo Monfrini
Summary: Parkinson's disease is the second most common neurodegenerative disorder among aging individuals and lacks disease-modifying therapy. The pathogenesis of Parkinson's disease involves dysfunction in several cellular mechanisms, with many monogenic forms resulting from pathogenic variants in genes related to endolysosomal function and synaptic vesicle trafficking. Additionally, studies have found a strong association between Parkinson's disease and lysosomal genes, indicating the significant role of lysosomal dysfunction in disease development. Understanding the mechanisms behind impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons is crucial for identifying therapeutic targets and developing effective drugs for modifying the neurodegenerative process.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Igor Bychkov, Alexandra Filatova, Grigory Perelman, Tatiana Proshlyakova, Daria Korotkova, Sergey Klyushnikov, Maria Karpova, Vyacheslav Tabakov, Galina Baydakova, Alexandra Ilyushkina, Mikhail Skoblov, Ekaterina Zakharova
Summary: Niemann-Pick disease type C (NP-C) is a rare lysosomal storage disorder caused by pathogenic variants in either the NPC1 or NPC2 genes, with complex clinical symptoms. Research shows that the impact of the frequent polymorphic variant is only significant in the presence of the rare synonymous variant.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2022)
Article
Neurosciences
T. S. Usenko, K. A. Senkevich, A. Bezrukova, G. Baydakova, K. S. Basharova, A. S. Zhuravlev, E. Gracheva, A. Kudrevatykh, I. Miliukhina, I. Krasakov, L. A. Khublarova, I. Fursova, D. Zakharov, A. A. Timofeeva, Y. A. Irishina, E. Palchikova, N. M. Zalutskaya, A. K. Emelyanov, E. Y. Zakharova, S. N. Pchelina
Summary: This study assessed changes in activities of enzymes involved in ceramide metabolism in different synucleinopathy patients and found significant alterations in lysosomal activities in MSA and DLB patients, supporting the role of lysosomal dysfunction in the pathogenesis of these diseases.
MOLECULAR NEUROBIOLOGY
(2022)
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
Biochemistry & Molecular Biology
Elena Voskoboeva, Alla Semyachkina, Ochir Miklyaev, Amina Gamzatova, Svetlana Mikhaylova, Nato Vashakmadze, Galina Baydakova, Olga Omzar, Natalia Pichkur, Ekaterina Zakharova, Sergey Kutsev
Summary: This study investigated the ARSB gene in MPS VI patients in Russia and other former Soviet Union republics, identifying 28 different pathogenic alleles. Two nucleotide changes were prevalent among Slavic Russian patients, while another nucleotide variant was specific to MPS VI families from the Republic of Dagestan. The study also showed a high frequency of the mutant allele in Dagestan, suggesting the feasibility of selective asymptomatic carrier testing and newborn screening in this region.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
E. Yu Voskoboeva, T. M. Bookina, A. N. Semyachkina, S. V. Mikhaylova, N. D. Vashakmadze, G. V. Baydakova, E. Yu Zakharova, S. I. Kutsev
Summary: This article presents the results of a molecular genetic study on 206 patients with mucopolysaccharidosis type I (MPS I) from the Russian Federation and other republics of the former Soviet Union. The study found differences in the distribution of IDUA gene mutations among different populations and ethnic groups. The identified features are important for understanding the molecular origin of the disease, predicting the risk of its development, and creating optimal diagnostic and treatment tools for specific regions and ethnic groups.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Cell Biology
Anastasiia Taraskina, Olga Ignatyeva, Darya Lisovaya, Mikhail Ivanov, Lyudmila Ivanova, Viktoriya Golovicheva, Galina Baydakova, Denis Silachev, Vasiliy Popkov, Tatyana Ivanets, Daria Kashtanova, Vladimir Yudin, Valentin Makarov, Ivan Abramov, Mariya Lukashina, Vera Rakova, Anzhelika Zagainova, Dmitry Zorov, Egor Plotnikov, Gennadiy Sukhikh, Sergey Yudin
Summary: Traumatic brain injury (TBI) has a significant impact on the body, affecting brain tissue, peripheral nervous system, and tissue homeostasis. This study investigates the brain-gut-microbiome axis in TBI using a rat model and bioinformatics analysis. The results show changes in bacterial abundance and metabolite concentrations due to TBI but no significant correlations with TBI severity. However, differences were found between subjects with high and low rates of neurological function recovery.
Article
Clinical Neurology
Viorica Chelban, Elham Nikram, Alexandra Perez-Soriano, Carlo Wilke, Alexandra Foubert-Samier, Nirosen Vijiaratnam, Tong Guo, Edwin Jabbari, Simisola Olufodun, Mariel Gonzalez, Konstantin Senkevich, Brice Laurens, Patrice Peran, Olivier Rascol, Anne Pavy Le Traon, Emily G. Todd, Alyssa A. Costantini, Sondos Alikhwan, Ambreen Tariq, Bai Lin Ng, Esteban Munoz, Celia Painous, Yaroslau Compta, Carme Junque, Barbara Segura, Kristina Zhelcheska, Henny Wellington, Ludger Schoels, Zane Jaunmuktane, Christopher Kobylecki, Alistair Church, Michele T. M. Hu, James B. Rowe, P. Nigel Leigh, Luke Massey, David J. Burn, Nicola Pavese, Tom Foltynie, Sofya Pchelina, Nicholas Wood, Amanda J. Heslegrave, Henrik Zetterberg, Martina Bocchetta, Jonathan D. Rohrer, Maria J. Marti, Matthis Synofzik, Huw R. Morris, Wassilios G. Meissner, Henry Houlden
Summary: In this study, it was found that plasma neurofilament light chain levels correlate with clinical disease severity, progression, and prognosis in multiple system atrophy, providing valuable information for patient stratification and treatment response monitoring in future trials. The use of neurofilament light chain as a biomarker in multiple system atrophy holds promise for improving trial outcomes and streamlining participant recruitment. Further research is warranted to fully understand the potential of neurofilament light chain in multiple system atrophy management.
Letter
Clinical Neurology
Alena E. Kopytova, Tatiana S. Usenko, Galina V. Baydakova, Mikhail A. Nikolaev, Konstantin A. Senkevich, Artem D. Izyumchenko, Alexandr A. Tyurin, Irina V. Miliukhina, Anton K. Emelyanov, Ekaterina Y. Zakharova, Sofya N. Pchelina
MOVEMENT DISORDERS
(2022)
Article
Medicine, General & Internal
Paria Alipour, Konstantin Senkevich, Jay P. Ross, Dan Spiegelman, Despoina Manousaki, Patrick A. Dion, Guy A. Rouleau
Summary: This study used Mendelian randomization (MR) to explore the causal relationship between autoimmune disorders and amyotrophic lateral sclerosis (ALS). The results showed that there is no relationship between liability to autoimmune disorders and ALS risk in the European population.
Letter
Clinical Neurology
Konstantin Senkevich, Ziv Gan-Or
MOVEMENT DISORDERS
(2022)
Article
Clinical Neurology
Konstantin Senkevich, Cornelia E. Zorca, Aliza Dworkind, Uladzislau Rudakou, Emma Somerville, Eric Yu, Alexey Ermolaev, Daria Nikanorova, Jamil Ahmad, Jennifer A. Ruskey, Farnaz Asayesh, Da Spiegelman, Stanley Fahn, Cheryl Waters, Oury Monchi, Yves Dauvilliers, Nicolas Dupre, Lior Greenbaum, Sharon Hassin-Baer, Francis P. Grenn, Ming Sum Ruby Chiang, S. Pablo Sardi, Benoit Vanderperre, Cornelis Blauwendraat, Jean-Francois Trempe, Edward A. Fon, Thomas M. Durcan, Roy N. Alcalay, Ziv Gan-Or
Summary: Senkevich et al. provide evidence that GALC is the gene associated with Parkinson's disease at the chromosome 14 locus and suggest that the association of variants at the GALC locus may be driven by their effect of increasing galactosylceramidase expression and activity. The study highlights the role of lysosome in Parkinson's disease pathogenesis.
Article
Clinical Neurology
Konstantin Senkevich, Paria Alipour, Ekaterina Chernyavskaya, Eric Yu, Alastair J. Noyce, Ziv Gan-Or
Summary: This study used genetic and epidemiological methods and found a potential genetic link between type 1 diabetes (T1D) and Parkinson's disease (PD), suggesting a potentially protective role of T1D in PD risk and progression.
MOVEMENT DISORDERS
(2023)
Article
Neurosciences
Hampton L. Leonard, Ruqaya Murtadha, Alejandro Martinez-Carrasco, Alina Jama, Amica Corda Mueller-Nedebock, Ana-Luisa Gil-Martinez, Anastasia Illarionova, Anni Moore, Bernabe I. Bustos, Bharati Jadhav, Brook Huxford, Catherine Storm, Clodagh Towns, Dan Vitale, Devina Chetty, Eric Yu, Francis P. Grenn, Gabriela Salazar, Geoffrey Rateau, Hirotaka Iwaki, Inas Elsayed, Isabelle Francesca Foote, Zune Jansen van Rensburg, Jonggeol Jeff Kim, Jie Yuan, Julie Lake, Kajsa Brolin, Konstantin Senkevich, Lesley Wu, Manuela M. X. Tan, Maria Teresa Perinan, Mary B. Makarious, Michael Ta, Nikita Simone Pillay, Oswaldo Lorenzo Betancor, Paula R. Reyes-Perez, Pilar Alvarez Jerez, Prabhjyot Saini, Rami al-Ouran, Ramiya Sivakumar, Raquel Real, Regina H. Reynolds, Ruifneg Hu, Shameemah Abrahams, Shilpa C. Rao, Tarek Antar, Thiago Peixoto Leal, Vassilena Iankova, William J. Scotton, Yeajin Song, Andrew Singleton, Mike A. Nalls, Sumit Dey, Sara Bandres-Ciga, Cornelis Blauwendraat, Alastair J. Noyce
Summary: Open science and collaboration are essential for Parkinson's disease (PD) research progress. Hackathons bring together people with diverse skills and backgrounds to generate resources and creative solutions. A virtual 3-day hackathon was organized, involving 49 early-career scientists from 12 countries who built PD-focused tools and pipelines. The goal was to provide scientists with access to necessary code and tools, accelerating their research. Hackathons inspire creative thinking, supplement data science training, and foster collaboration, benefiting early-career researchers. The generated resources can accelerate PD genetics research.
NPJ PARKINSONS DISEASE
(2023)
Meeting Abstract
Biochemistry & Molecular Biology
Igor Bychkov, Aleksandra Filatova, Tatiana Proshlyakova, Vyacheslav Tabakov, Galina Baydakova, Alexandra Ilyushkina, Mikhail Skoblov, Ekaterina Zakharova
EUROPEAN JOURNAL OF HUMAN GENETICS
(2022)
