Article
Biochemistry & Molecular Biology
Marta Vranas, Yang Lu, Shafqat Rasool, Nathalie Croteau, Jonathan D. Krett, Veronique Sauve, Kalle Gehring, Edward A. Fon, Thomas M. Durcan, Jean-Francois Trempe
Summary: Mutations in Parkin and PINK1 cause early-onset familial Parkinson's disease. The study found that His433 contributes to the catalysis of Parkin and its mutation impairs mitophagy. Mfn2 is a kinetically preferred substrate for Parkin, co-localizing with PINK1 and phospho-ubiquitin upon mitochondrial depolarization.
Article
Cell Biology
Fabienne C. Fiesel, Dominika Fricova, Caleb S. Hayes, Mathew A. Coban, Roman Hudec, Jenny M. Bredenberg, Benjamin J. Broadway, Briana N. Markham, Tingxiang Yan, Paige K. Boneski, Gabriella Fiorino, Jens O. Watzlawik, Xu Hou, Arthur M. McCarty, Laura J. Lewis-Tuffin, Jun Zhong, Benjamin J. Madden, Alban Ordureau, Heeseon An, Andreas Puschmann, Zbigniew K. Wszolek, Owen A. Ross, J. Wade Harper, Thomas R. Caulfield, Wolfdieter Springer
Summary: This study investigates the impact of single nucleotide variants in the activation loop of the PINK1 kinase on its enzymatic function. The G411A variant of PINK1 is found to significantly enhance Ub phosphorylation and promote PRKN activation and mitophagy, leading to increased neuronal viability under mitochondrial stress. The mechanism involves the stabilization of PINK1's kinase fold and a change in Ub conformation. These findings suggest that the G411A variant could have therapeutic potential for neuroprotection.
Article
Cell Biology
Jens O. Watzlawik, Fabienne C. Fiesel, Gabriella Fiorino, Bernardo A. Bustillos, Zahra Baninameh, Briana N. Markham, Xu Hou, Caleb S. Hayes, Jenny M. Bredenberg, Nicholas W. Kurchaba, Dominika Fricova, Joanna Siuda, Zbigniew K. Wszolek, Sachiko Noda, Shigeto Sato, Nobutaka Hattori, Asheeta A. Prasad, Deniz Kirik, Howard S. Fox, Kelly L. Stauch, Matthew S. Goldberg, Wolfdieter Springer
Summary: This study investigates the basal activation levels of the PINK1-PRKN signaling pathway in vivo using rodent samples, patient-derived cells, and isogenic neurons. The findings highlight the age-dependent, brain region-specific, and cell type-specific effects of PINK1-PRKN signaling, which have significant implications for improving diagnosis, prognosis, and patient stratification in Parkinson's disease.
Review
Neurosciences
Iryna Kamienieva, Jerzy Duszynski, Joanna Szczepanowska
Summary: The familial form of Parkinson's disease is linked to mutations in specific genes, with mutations in the parkin gene being one of the most common causes of early-onset PD. Mitochondrial dysfunction is an emerging active player in the pathology of neurodegenerative diseases, as mitochondria are highly dynamic structures integrated with many cellular functions.
TRANSLATIONAL NEURODEGENERATION
(2021)
Review
Chemistry, Multidisciplinary
Guy Mann, Pradeep Sadhu, Ashraf Brik
Summary: This article discusses recent advances in protein delivery methods, with a focus on those most compatible with synthetic proteins. Researchers have been working on developing protein delivery methods to study custom-made proteins in a biological context. These methods can help accurately determine the localization, degradation, folding, interactions, and involvement of proteins in membrane-less organelles formed by liquid-liquid phase separation inside cells.
ACCOUNTS OF CHEMICAL RESEARCH
(2022)
Article
Cell Biology
James L. Shen, Tina M. Fortier, Ruoxi Wang, Eric H. Baehrecke
Summary: Defects in autophagy can lead to issues in metabolism, development, and disease. The loss of Vps13D affects mitophagy, regulated by the core autophagy machinery. Pink1 and Vps13D play roles in Pink1-dependent mitophagy, with Park contributing to mitochondrial clearance through a pathway parallel to Vps13D.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Biology
Emma Rusilowicz-Jones, Francesco G. Barone, Fernanda Martins Lopes, Elezabeth Stephen, Heather Mortiboys, Sylvie Urbe, Michael J. Clague
Summary: Compound 39 inhibits USP30 and enhances mitophagy and pexophagy, providing a novel pharmacological intervention for enhancing peroxisome turnover. "This is the first pharmacological intervention with a synthetic molecule to enhance peroxisome turnover."
LIFE SCIENCE ALLIANCE
(2022)
Review
Biochemistry & Molecular Biology
Tohru Kitada, Mustafa T. Ardah, M. Emdadul Haque
Summary: Parkin, discovered 25 years ago as the gene responsible for hereditary Parkinson's disease, remains a subject of intense research interest. Despite extensive efforts, the function and mechanism of the Parkin protein in neuronal cell death and pathogenesis remain unknown. This review highlights the chronological research on the parkin gene and discusses unresolved issues, new trends in research, and the relationship between parkin and tumorigenesis from the perspective of Parkin's redox molecule.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Rajesh Kumar, Andreas S. Reichert
Summary: Mitochondria are essential organelles in eukaryotic cells involved in various cellular functions, and dysfunction is linked to several diseases. Both yeast and mammals utilize similar mechanisms to regulate mitophagy, a process of degrading damaged mitochondria.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Myungsik Yoo, Doo Chul Choi, Aleta Murphy, Atiq M. Ahsan, Eunsung Junn
Summary: Neurodegenerative diseases involve the decline and death of neurons, and understanding the molecular mechanisms behind neuronal death is important for therapeutic development. MiRs are small RNAs that regulate gene expression, and their dysregulation has been linked to neurodegenerative diseases. In this study, the researchers investigated miR-593-5p and its role in neuronal death caused by mitochondrial dysfunction. They found that miR-593-5p was increased in response to exposure to MPP+ and contributed to cell death by inhibiting a pathway involving PINK1 and Parkin. These findings suggest that miR-593-5p may be a potential therapeutic target for neurodegenerative diseases.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Chi-Jing Choong, Hideki Mochizuki, Cesar Borlongan
Summary: Mitochondrial dysregulation is strongly associated with the pathogenesis of Parkinson's disease (PD), with mutated genes affecting mitochondrial features. Disruption of mitochondrial quality control and abnormal secretion of mitochondrial contents play a role in PD, and circulating mitochondrial DNAs can elicit inflammatory response.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Benjamin J. Broadway, Paige K. Boneski, Jenny M. Bredenberg, Ana Kolicheski, Xu Hou, Alexandra Soto-Beasley, Owen A. Ross, Wolfdieter Springer, Fabienne C. Fiesel
Summary: Loss of PINK1 or PRKN can cause early onset Parkinson's disease. Through analyzing a set of variants, this study identifies specific rare genetic PINK1 and PRKN variants that result in loss of enzymatic function and suggests their potential causative role in Parkinson's disease. Additionally, the study finds intermediate phenotypes in several variants and investigates the functional deficits of two variants using gene editing. The findings of this study contribute to the diagnostics and treatment of Parkinson's disease.
Article
Clinical Neurology
Jannik Prasuhn, Meike Kasten, Melissa Vos, Inke R. Koenig, Sebastian M. Schmid, Britta Wilms, Christine Klein, Norbert Brueggemann
Summary: This study aims to investigate the potential effects of vitamin K2 on genetically determined Parkinson's disease patients, using advanced neuroimaging methods and biomarker sampling. Patients are selected based on mutation-related mitochondrial dysfunction in a personalized medicine approach and the study will explore the predictive ability of neuroimaging and blood-derived biomarkers on individual treatment response in sporadic PD.
FRONTIERS IN NEUROLOGY
(2021)
Article
Cell Biology
Jens O. Watzlawik, Xu Hou, Dominika Truban, Chloe Ramnarine, Sandeep K. Barodia, Tania F. Gendron, Michael G. Heckman, Michael DeTure, Joanna Siuda, Zbigniew K. Wszolek, Clemens R. Scherzer, Owen A. Ross, Guojun Bu, Dennis W. Dickson, Matthew S. Goldberg, Fabienne C. Fiesel, Wolfdieter Springer
Summary: Mitochondrial dysfunction is an early event in neurodegenerative disorders like Parkinson's and Alzheimer's disease. Researchers developed a sensitive ELISA tool to measure mitophagy levels and found that the PINK1-PRKN mitophagy pathway is actively involved in both mice and humans under various physiological and pathological conditions.
Article
Cell Biology
Takayuki Mito, Amy E. Vincent, Julie Faitg, Robert W. Taylor, Nahid A. Khan, Thomas G. McWilliams, Anu Suomalainen
Summary: The study finds that mitophagy plays a significant role in skeletal muscle mitochondrial dysfunction in aged mice and human patients. The progression of mitochondrial dysfunction interrupts mitophagy and disrupts lysosomal homeostasis. The mosaic halting of mitophagy may explain respiratory chain deficiency and accumulation of mtDNA variants in mitochondrial diseases and normal aging.
Article
Biochemistry & Molecular Biology
Lukasz M. Milanowski, Xu Hou, Jenny M. Bredenberg, Fabienne C. Fiesel, Liam T. Cocker, Alexandra Soto-Beasley, Ronald L. Walton, Audrey J. Strongosky, Ayman H. Faroqi, Maria Barcikowska, Magdalena Boczarska-Jedynak, Jaroslaw Dulski, Lyuda Fedoryshyn, Piotr Janik, Anna Potulska-Chromik, Katherine Karpinsky, Anna Krygowska-Wajs, Tim Lynch, Diana A. Olszewska, Grzegorz Opala, Aleksander Pulyk, Irena Rektorova, Yanosh Sanotsky, Joanna Siuda, Mariusz Widlak, Jaroslaw Slawek, Monika Rudzinska-Bar, Ryan Uitti, Monika Figura, Stanislaw Szlufik, Sylwia Rzonca-Niewczas, Elzbieta Podgorska, Pamela J. McLean, Dariusz Koziorowski, Owen A. Ross, Dorota Hoffman-Zacharska, Wolfdieter Springer, Zbigniew K. Wszolek
Summary: This study identified a potential genetic cause of Parkinson's disease in two affected siblings. However, functional analysis of patient-derived fibroblasts did not reveal significant changes, suggesting that the CTSB gene may harbor variants with different penetrance that can determine disease risk.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Benjamin J. Broadway, Paige K. Boneski, Jenny M. Bredenberg, Ana Kolicheski, Xu Hou, Alexandra Soto-Beasley, Owen A. Ross, Wolfdieter Springer, Fabienne C. Fiesel
Summary: Loss of PINK1 or PRKN can cause early onset Parkinson's disease. Through analyzing a set of variants, this study identifies specific rare genetic PINK1 and PRKN variants that result in loss of enzymatic function and suggests their potential causative role in Parkinson's disease. Additionally, the study finds intermediate phenotypes in several variants and investigates the functional deficits of two variants using gene editing. The findings of this study contribute to the diagnostics and treatment of Parkinson's disease.
Article
Cell Biology
Fabienne C. Fiesel, Dominika Fricova, Caleb S. Hayes, Mathew A. Coban, Roman Hudec, Jenny M. Bredenberg, Benjamin J. Broadway, Briana N. Markham, Tingxiang Yan, Paige K. Boneski, Gabriella Fiorino, Jens O. Watzlawik, Xu Hou, Arthur M. McCarty, Laura J. Lewis-Tuffin, Jun Zhong, Benjamin J. Madden, Alban Ordureau, Heeseon An, Andreas Puschmann, Zbigniew K. Wszolek, Owen A. Ross, J. Wade Harper, Thomas R. Caulfield, Wolfdieter Springer
Summary: This study investigates the impact of single nucleotide variants in the activation loop of the PINK1 kinase on its enzymatic function. The G411A variant of PINK1 is found to significantly enhance Ub phosphorylation and promote PRKN activation and mitophagy, leading to increased neuronal viability under mitochondrial stress. The mechanism involves the stabilization of PINK1's kinase fold and a change in Ub conformation. These findings suggest that the G411A variant could have therapeutic potential for neuroprotection.
Article
Biochemistry & Molecular Biology
Zhixiao Wu, Lena A. Berlemann, Verian Bader, Dominik A. Sehr, Eva Dawin, Alberto Covallero, Jens Meschede, Lena Angersbach, Cathrin Showkat, Jonas B. Michaelis, Christian Muench, Bettina Rieger, Dmitry Namgaladze, Maria Georgina Herrera, Fabienne C. Fiesel, Wolfdieter Springer, Marta Mendes, Jennifer Stepien, Katalin Barkovits, Katrin Marcus, Albert Sickmann, Gunnar Dittmar, Karin B. Busch, Dietmar Riedel, Marisa Brini, Joerg Tatzelt, Tito Cali, Konstanze F. Winklhofer
Summary: Recent research has revealed the importance of mitochondria in cellular metabolism, redox homeostasis, and cell fate decisions, as well as in innate immune signaling. This study demonstrates that the NF-kappa B pathway activated by TNF utilizes mitochondria as a platform for signal amplification and transport of activated NF-kappa B to the nucleus. The findings highlight the role of mitochondria in regulating immune signaling pathways.
Review
Neurosciences
Ana Kolicheski, Pierpaolo Turcano, Nicole Tamvaka, Pamela J. McLean, Wolfdieter Springer, Rodolfo Savica, Owen A. Ross
Summary: Parkinson's disease is a late-onset movement disorder, but early-onset cases are influenced by a combination of genetic and environmental factors. Integrating genetic and environmental data is important to understand the etiology and determine the interaction between different pathogenic mechanisms.
JOURNAL OF PARKINSONS DISEASE
(2022)
Article
Oncology
Sikander Ailawadhi, Ricardo D. Parrondo, Navnita Dutta, Bing Han, Gina Ciccio, Yesesri Cherukuri, Victoria R. Alegria, Betsy R. LaPlant, Vivek Roy, Taimur Sher, Brett Edwards, Stephanie Lanier, Alak Manna, Keisha Heslop, Thomas Caulfield, Emir Maldosevic, Peter Storz, Rami Manochakian, Yan Asmann, Asher A. Chanan-Khan, Aneel Paulus
Summary: Bcl-2 family proteins play a crucial role in myeloma cell survival and are potential therapeutic targets. The combination of AT-101, lenalidomide, and dexamethasone (ARd regimen) demonstrates promising efficacy and safety in relapsed/refractory multiple myeloma patients, with positive effects on tumor burden reduction and immune cell modulation.
Article
Biochemistry & Molecular Biology
Seth Osei Asiedu, Yash Gupta, Vlad Nicolaescu, Haley Gula, Thomas R. Caulfield, Ravi Durvasula, Prakasha Kempaiah, Samuel K. Kwofie, Michael D. Wilson
Summary: We previously demonstrated that Mycolactone (MLN), a toxin produced by Mycobacterium ulcerans, binds strongly to Munc18b and other proteins, potentially inhibiting degranulation and exocytosis. In this study, we investigated MLN's effects on endocytosis and found that it strongly binds to the N-terminal of the clathrin protein and a novel SARS-CoV-2 fusion protein.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biology
Michael U. Stevens, Nathalie Croteau, Mohamed A. Eldeeb, Odetta Antico, Zhi Wei Zeng, Rachel Toth, Thomas M. Durcan, Wolfdieter Springer, Edward A. Fon, Miratul M. K. Muqit, Jean-Francois Tremple
Summary: Autosomal recessive mutations in the Parkin gene cause Parkinson's disease. Parkin encodes an ubiquitin E3 ligase that functions together with the kinase PINK1 in a mitochondrial quality control pathway. In this study, new activating mutations were designed in both human and rat Parkin across interdomain interfaces. The identified activating mutations suggest potential therapeutic targets for Parkinson's disease patients with select Parkin mutations.
LIFE SCIENCE ALLIANCE
(2023)
Article
Genetics & Heredity
Anna N. Ligezka, Rohit Budhraja, Yurika Nishiyama, Fabienne C. Fiesel, Graeme Preston, Andrew Edmondson, Wasantha Ranatunga, Johan L. K. Van Hove, Jens O. Watzlawik, Wolfdieter Springer, Akhilesh Pandey, Eva Morava, Tamas Kozicz
Summary: This article investigates the changes in mitochondrial function and autophagy/mitophagy in PMM2-CDG patients. The study reveals secondary mitochondrial dysfunction and altered autophagy in PMM2-CDG patient-derived fibroblast lines. These findings suggest a potential correlation between autophagy and disease severity in PMM2-CDG.
Article
Cell Biology
Jens O. Watzlawik, Fabienne C. Fiesel, Gabriella Fiorino, Bernardo A. Bustillos, Zahra Baninameh, Briana N. Markham, Xu Hou, Caleb S. Hayes, Jenny M. Bredenberg, Nicholas W. Kurchaba, Dominika Fricova, Joanna Siuda, Zbigniew K. Wszolek, Sachiko Noda, Shigeto Sato, Nobutaka Hattori, Asheeta A. Prasad, Deniz Kirik, Howard S. Fox, Kelly L. Stauch, Matthew S. Goldberg, Wolfdieter Springer
Summary: This study investigates the basal activation levels of the PINK1-PRKN signaling pathway in vivo using rodent samples, patient-derived cells, and isogenic neurons. The findings highlight the age-dependent, brain region-specific, and cell type-specific effects of PINK1-PRKN signaling, which have significant implications for improving diagnosis, prognosis, and patient stratification in Parkinson's disease.