Review
Clinical Neurology
Paolo Calabresi, Giulia Di Lazzaro, Gioia Marino, Federica Campanelli, Veronica Ghiglieri
Summary: The critical role of alpha-synuclein in Parkinson's disease has been discovered, but current treatments still face challenges. Developing cellular and animal models helps understand the physiological and pathological functions of alpha-synuclein, as well as the pathogenesis of Parkinson's disease.
Article
Chemistry, Multidisciplinary
Yu-Lin Guo, Wen-Jun Duan, Dan-Hua Lu, Xiao-Hui Ma, Xiao-Xiao Li, Zhao Li, Wei Bi, Hiroshi Kurihara, Hai-Zhi Liu, Yi-Fang Li, Rong-Rong He
Summary: GM1 ganglioside has therapeutic effects in experimental models of Parkinson's disease by promoting autophagy to clear harmful protein α-Syn, alleviating symptoms of neurodegenerative diseases like Parkinson's disease.
ACTA PHARMACOLOGICA SINICA
(2021)
Article
Clinical Neurology
Thomas Steinkellner, William S. Conrad, Imre Kovacs, Robert A. Rissman, Edward B. Lee, John Q. Trojanowski, Zachary Freyberg, Subhojit Roy, Kelvin C. Luk, Virginia M. Lee, Thomas S. Hnasko
Summary: VGLUT2-expressing dopamine neurons exhibit resilience to degeneration and may be part of a neuroprotective response in Parkinson's disease.
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
Biochemistry & Molecular Biology
Antonella Cardinale, Valeria Calabrese, Antonio de Iure, Barbara Picconi
Summary: Parkinson's disease is characterized by the aggregation of alpha-synuclein protein in brain regions and the loss of dopaminergic neurons, which leads to synaptic alterations and immune system activation. Toxic species of alpha-syn, such as oligomers and protofibrils, impair synaptic protein distribution and neurotransmitter release, while inflammatory response mediated by microglia and astrocytes is linked to alpha-syn accumulation in the central nervous system.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Toxicology
Jie Chen, Xufang Gao, Chengyou Zheng, Chen Zhang, Peimao Li, Kaiwu He, Gongping Liu, Xinfeng Huang, Jianjun Liu, Yongmei Xie, Xifei Yang
Summary: Low-dose copper treatment alters critical proteins involved in mitochondrial, neurodevelopmental, and inflammatory responses, and affects levels of ROS and ATP production in mitochondria.
TOXICOLOGY LETTERS
(2023)
Review
Clinical Neurology
Kenya Nishioka, Yuzuru Imai, Hiroyo Yoshino, Yuanzhe Li, Manabu Funayama, Nobutaka Hattori
Summary: Research has identified over 20 genes related to familial Parkinson's disease, shedding light on its molecular basis and pathological mechanisms. Along with genes associated with PD, molecular mechanisms related to dopamine synthesis, oxidative stress, mitochondrial maintenance, etc., have also been discovered.
FRONTIERS IN NEUROLOGY
(2022)
Article
Immunology
Adrianne F. Pike, Francesca Longhena, Gaia Faustini, Jean-Marc Van Eik, Iris Gombert, Maaike A. C. Herrebout, Mona M. H. E. Fayed, Michele Sandre, Tatiana Varanita, Charlotte E. Teunissen, Jeroen J. M. Hoozemans, Arianna Bellucci, Robert Veerhuis, Luigi Bubacco
Summary: This study reveals that dopamine inhibits the activation of NLRP3 inflammasome in primary human microglia, providing insights into the potential therapeutic target for Parkinson's disease.
JOURNAL OF NEUROINFLAMMATION
(2022)
Article
Biochemistry & Molecular Biology
Artur M. Coutinho, Maria Gabriela Ghilardi, Ana Carolina P. Campos, Elba Etchebehere, Fernanda C. Fonoff, Rubens G. Cury, Rosana L. Pagano, Raquel C. R. Martinez, Erich T. Fonoff
Summary: This study aimed to understand the correlation between disease laterality, DAT-SPECT, cognition, and alpha-synuclein levels in PD. The results showed that alpha-synuclein in the CSF was correlated with global cognition and DAT-SPECT concentration in specific brain regions, thus working as a neurodegenerative biomarker.
Review
Biochemistry & Molecular Biology
Tapan Behl, Piyush Madaan, Aayush Sehgal, Sukhbir Singh, Md Khalid Anwer, Hafiz A. Makeen, Mohammed Albratty, Syam Mohan, Simona Bungau
Summary: This article discusses the etiology, oxidative stress, autophagy, programmed cell death, and other important roles in the pathogenesis of Parkinson's disease, emphasizing the crucial role of iron and copper in the development of Parkinson's disease. Metal chelators may have the potential to reduce oxidative stress levels by scavenging metal ions, thereby preventing or slowing down the progression of Parkinson's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Min Lin, Phillip M. Mackie, Fatima Shaerzadeh, Joyonna Gamble-George, Douglas R. Miller, Chris J. Martyniuk, Habibeh Khoshbouei
Summary: Pathophysiological changes in dopamine neurons caused by overexpression of alpha-synuclein lead to dysfunction of D2 receptors, resulting in aberrant firing activity, dopamine release, and neuronal morphology, which can be partially restored by D2 receptor agonists such as quinpirole.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
Article
Medicine, General & Internal
G. Pagano, K. I. Taylor, J. Anzures-Cabrera, M. Marchesi, T. Simuni, K. Marek, R. B. Postuma, N. Pavese, F. Stocchi, J. -P. Azulay, B. Mollenhauer, L. Lopez-Manzanares, D. S. Russell, J. T. Boyd, A. P. Nicholas, M. R. Luquin, R. A. Hauser, T. Gasser, W. Poewe, B. Ricci, A. Boulay, A. Vogt, F. G. Boess, J. Dukart, G. D'Urso, R. Finch, S. Zanigni, A. Monnet, N. Pross, A. Hahn, H. Svoboda, M. Britschgi, F. Lipsmeier, E. Volkova-Volkmar, M. Lindemann, S. Dziadek, S. Holiga, D. Rukina, T. Kustermann, G. A. Kerchner, P. Fontoura, D. Umbricht, R. Doody, T. Nikolcheva, A. Bonni
Summary: The study found that prasinezumab had no meaningful effect on global or imaging measures of Parkinson's disease progression and was associated with infusion reactions.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Multidisciplinary Sciences
Hideaki Matsui, Shinji Ito, Hideki Matsui, Junko Ito, Ramil Gabdulkhaev, Mika Hirose, Tomoyuki Yamanaka, Akihide Koyama, Taisuke Kato, Maiko Tanaka, Norihito Uemura, Noriko Matsui, Sachiko Hirokawa, Maki Yoshihama, Aki Shimozawa, Shin-ichiro Kubo, Kenji Iwasaki, Masato Hasegawa, Ryosuke Takahashi, Keisuke Hirai, Akiyoshi Kakita, Osamu Onodera
Summary: This study found that phosphorylation of a-Synuclein at T64 was increased in both Parkinson's disease models and human PD brains. The T64D phosphomimetic mutation led to the formation of a-Synuclein oligomers with a similar structure to those with the A53T mutation, and it induced mitochondrial dysfunction, lysosomal disorder, cell death, and neurodegeneration. These findings suggest a pathogenic role of a-Synuclein phosphorylation at T64 in Parkinson's disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(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)
Article
Biochemistry & Molecular Biology
Mari Suzuki, Kazunori Sango, Yoshitaka Nagai
Summary: Alpha-synuclein plays a major role in the pathogenesis of Parkinson's disease, and fruit fly models expressing alpha-synuclein contribute to the understanding of disease-associated factors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Alice Filippini, Veronica Mutti, Gaia Faustini, Francesca Longhena, Ileana Ramazzina, Federica Rizzi, Alice Kaganovich, Dorien A. Roosen, Natalie Landeck, Megan Duffy, Isabella Tessari, Federica Bono, Chiara Fiorentini, Elisa Greggio, Luigi Bubacco, Arianna Bellucci, Mariacristina Missale, Mark R. Cookson, Massimo Gennarelli, Isabella Russo
Summary: The progressive neuropathological damage in Parkinson's disease is believed to be related to the spread of aggregated forms of alpha-synuclein. Clearance of extracellular alpha-synuclein by neurons may be a key mechanism to control its concentration. Clusterin, a glycoprotein associated with Alzheimer's disease, interacts with alpha-synuclein aggregates and limits their uptake by astrocytes, which may contribute to the spreading of Parkinson's pathology.
Article
Chemistry, Multidisciplinary
Giulia Marafon, Marco Crisma, Anna Masato, Nicoletta Plotegher, Luigi Bubacco, Alessandro Moretto
Summary: Proteins undergo changes in their 3D structure and function through specific molecular interactions, which is crucial for sensing, processing, and transmitting information from the surrounding environment. The study of early aggregation steps of alpha-synuclein associated with Parkinson's disease showed that light-mediated binding with a photoactive foldamer can promote the process by generating supramolecular fibrillar seeds that act as molecular templates for inducing fast beta-sheet transitions in monomers. This proposed method provides a powerful tool for studying protein aggregation in misfolding diseases in a controlled and inducible system.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Elina Buitrago, Clarisse Faure, Lylia Challali, Elisabetta Bergantino, Ahcene Boumendjel, Luigi Bubacco, Marcello Carotti, Renaud Hardre, Marc Maresca, Christian Philouze, Helene Jamet, Marius Reglier, Catherine Belle
Summary: In this study, a combination of known inhibitors targeting the binuclear copper active site on tyrosinases was investigated, revealing significant enhancement of inhibitory effects, particularly for the HOPNO-TSC compound. The interaction mode with the dicopper(II) active site was elucidated through binding studies with a tyrosinase bio-inspired model, showing that binding to the dicopper center can occur with both chelating sites. Computational and docking studies identified the kojic acid and HOPNO moieties as interacting groups with the dicopper active site.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Review
Biochemistry & Molecular Biology
Federica De Lazzari, Hiran A. Prag, Anja V. Gruszczyk, Alexander J. Whitworth, Marco Bisaglia
Summary: DJ-1 is a multifunctional protein implicated in various diseases, with therapeutic potential in ischemia-reperfusion injury.
Review
Biochemistry & Molecular Biology
Francesco Agostini, Anna Masato, Luigi Bubacco, Marco Bisaglia
Summary: This article reviews the potential mechanisms and clinical applications of metformin in the treatment of Parkinson's disease. Studies have shown that metformin may exert neuroprotective effects by regulating cellular pathways such as autophagy, degradation of pathological proteins, and mitochondrial function. Epidemiological studies on the correlation between long-term metformin use and the risk of developing Parkinson's disease are also discussed. However, there is controversy regarding the results obtained from experimental models and clinical studies, and further research is needed to clarify the mechanisms and efficacy of metformin in the treatment of Parkinson's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Liaisan Arslanbaeva, Marco Bisaglia
Summary: This review discusses the role of the Nrf2 pathway in the pathogenesis of ALS and the modulation of this protective pathway by astrocytes. It also introduces the currently developed Nrf2 activators, including their potentials and limitations in both preclinical animal models and clinical studies.
Review
Neurosciences
Adrianne F. Pike, Ildiko Szabo, Robert Veerhuis, Luigi Bubacco
Summary: This review suggests a hypothesis that Kv1.3 activity-induced NLRP3 inflammasome activation in microglia may be counteracted by the utilization of dopamine from adjacent dopaminergic neurons, preventing microglial activation. However, as dopamine supply decreases, NLRP3 inflammasome activation and Kv1.3 activity would intensify, leading to the development of the major pathological features of Parkinson's disease.
NPJ PARKINSONS DISEASE
(2022)
Article
Chemistry, Multidisciplinary
Andrea Capucciati, Enrico Monzani, Michela Sturini, Stefania Nicolis, Fabio A. Zucca, Luigi Bubacco, Marco Bortolus, Luigi Zecca, Luigi Casella
Summary: The study uses water-soluble melanin-protein-Fe/Cu conjugates derived from norepinephrine and fibrillar beta-lactoglobulin as reliable models for human brain locus coeruleus neuromelanin (NM). Iron and copper promote catecholamine oxidation and tend to remain coupled in oligonuclear aggregates. The Fe-Cu clusters are EPR silent and affect the H-1 NMR spectra of the conjugates.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Federica De Lazzari, Francesco Agostini, Davide Doni, Sandro Malacrida, Mauro A. Zordan, Paola Costantini, Luigi Bubacco, Federica Sandrelli, Marco Bisaglia
Summary: Redox homeostasis plays a vital role in various pathological processes, including neurodegenerative disorders. SOD1 and DJ-1 are key enzymes involved in the antioxidant response, and they play important roles in the maturation process of proteins. Our study demonstrates that the protective activity of DJ-1 in fruit flies is independent of SOD1, suggesting different mechanisms of action.
Review
Biochemistry & Molecular Biology
Marco Bisaglia
Summary: Parkinson's disease is an age-related neurodegenerative disorder characterized by motor disturbances and non-motor symptoms. There is growing attention on the role of the gut-brain axis and alterations in the gut microbiota in the development of PD. The Mediterranean diet, with its antioxidant and anti-inflammatory properties, as well as its effects on the microbiota composition, has been shown to influence both the onset and progression of PD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Federica Sandrelli, Marco Bisaglia
Summary: Amyotrophic lateral sclerosis (ALS) is a progressive disease that primarily affects the motor neurons of the cortex and spinal cord, resulting in death a few years after symptom onset. While most cases of ALS are sporadic, about 5-10% have a genetic component. The study of ALS-associated genes, particularly mutations in the DJ-1 gene, has provided insights into the pathological mechanisms of both familial and sporadic ALS. DJ-1 is involved in various cellular functions related to oxidative stress, mitochondrial homeostasis, energy metabolism, and hypoxia response, which may contribute to the development and progression of ALS. Targeting these pathways could potentially offer therapeutic strategies for ALS prevention and treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Sasanka Chakrabarti, Marco Bisaglia
Summary: Parkinson's disease is a chronic neurodegenerative condition that affects over 1% of people over the age of 65. It is characterized by the degeneration of specific neurons responsible for motor symptoms. The underlying mechanisms, including redox alterations, mitochondrial dysfunctions, and neuroinflammation, are not fully understood. This review explores the role of dopamine and its oxidation chemistry in the pathogenesis of Parkinson's disease, including the formation of free radicals and toxic metabolites.
Review
Biochemistry & Molecular Biology
Francesco Agostini, Marco Bisaglia, Nicoletta Plotegher
Summary: Reactive oxygen species (ROS) generated from incomplete oxygen reduction can interact with and influence the function of various targets, including DNA, lipids, and proteins. AMP-activated protein kinase (AMPK), known as a major sensor of intracellular energy status, has been shown to play a crucial role in regulating cellular processes such as autophagy and lysosomal function. Through its modulation, AMPK can participate in the crosstalk between mitochondria and lysosomes by perceiving signals related to mitochondrial dynamics and transducing them to lysosomes, thereby impacting autophagic flux. Future studies should focus on the specific contribution of different AMPK subpopulations to the autophagic pathway, considering the tissue-specific regulation and localization of AMPK.
