Article
Cardiac & Cardiovascular Systems
Andrea D. Thompson, Marcus J. Wagner, Juliani Rodriguez, Alok Malhotra, Steve Vander Roest, Ulla Lilienthal, Hao Shao, Mathav Vignesh, Keely Weber, Jaime M. Yob, Benjamin L. Prosser, Adam S. Helms, Jason E. Gestwicki, David Ginsburg, Sharlene M. Day
Summary: This study identifies the heat shock protein 70-BAG3 complex as a regulator of MyBP-C stability in familial hypertrophic cardiomyopathy. The findings suggest potential therapeutic strategies for this condition.
JACC-BASIC TO TRANSLATIONAL SCIENCE
(2023)
Article
Clinical Neurology
Nicolae Grecu, Luisa Villa, Michele Cavalli, Antoine Ristaino, Ariane Choumert, Catherine Butori, Leonardo Salviati, Angela Puma, Sabrina Sacconi, Martin Krahn, Mathieu Cerino
Summary: GNE gene mutations may be associated with motor neuropathy, resulting in varying degrees of nerve involvement. All patients showed GNE gene mutations in genetic testing, leading to different degrees of muscle weakness.
Review
Cell Biology
Barbara Tedesco, Leen Vendredy, Vincent Timmerman, Angelo Poletti
Summary: Each protein must be correctly synthesized, folded, and transported to its appropriate location. Failure in these steps can lead to protein misfolding and potential damage. Cells have well-characterized protein quality control systems, including autophagy and chaperone-assisted selective autophagy (CASA), to minimize such issues. The CASA complex, composed of HSPA, HSPB8, and BAG3 proteins, is essential for maintaining protein homeostasis and mutations in these genes can result in (cardio)myopathies and neurodegenerative diseases. This article summarizes the current understanding of the CASA complex and discusses its involvement in diseases and potential therapeutic targets.
Article
Cell Biology
Elena Casarotto, Daisy Sproviero, Eleonora Corridori, Maria Cristina Gagliani, Marta Cozzi, Marta Chierichetti, Riccardo Cristofani, Veronica Ferrari, Mariarita Galbiati, Francesco Mina, Margherita Piccolella, Paola Rusmini, Barbara Tedesco, Stella Gagliardi, Katia Cortese, Cristina Cereda, Angelo Poletti, Valeria Crippa
Summary: Extracellular vesicles (EVs) play a crucial role in neurodegenerative diseases by either spreading pathological proteins or participating in the clearance of disease-associated proteins. This study found that both large and small EVs contain TDP-43 species, and the secretion of TDP-35 and TDP-25 is increased when the protein quality control (PQC) system is inhibited. Additionally, EVs transport components of the chaperone-assisted selective autophagy (CASA) complex, highlighting a potential new role for CASA complex in neurodegenerative diseases.
Article
Genetics & Heredity
Hans-Juergen Kreienkamp, Matias Wagner, Heike Weigand, Allyn McConkie-Rossell, Marie McDonald, Boris Keren, Cyril Mignot, Julie Gauthier, Jean-Francois Soucy, Jacques L. Michaud, Meghan Dumas, Rosemarie Smith, Ulrike Loebel, Maja Hempel, Christian Kubisch, Jonas Denecke, Philippe M. Campeau, Jennifer M. Bain, Davor Lessel
Summary: The study identified male individuals with pathogenic or likely pathogenic variants in the HNRNPH2 gene, some showing mild developmental delay and autistic features, while others had severe neurodevelopmental delay and seizures. Functional analysis and RNA sequencing revealed the impact of the variants on protein function and gene expression.
Article
Biochemistry & Molecular Biology
Kyong-hwa Kang, Ji Eun Han, Hyunjin Kim, Sohee Kim, Young Bin Hong, Jeanho Yun, Soo Hyun Nam, Byung-Ok Choi, Hyongjong Koh
Summary: Charcot-Marie-Tooth disease (CMT) is a group of inherited peripheral nerve disorders characterized by muscle weakness, sensory loss, foot deformities and gait abnormalities. Missense mutations in the HSPB8 gene have been associated with hereditary neuropathies, including CMT. In this study, HSPB8 mutant-induced neuropathies were modeled in Drosophila, revealing motor defects and mitochondrial dysfunction. The motor defects and mitochondrial dysfunction were restored by PINK1 and parkin, as well as a small molecule called kinetin riboside.
Article
Cell Biology
I-Hui Wu, Jae Seok Yoon, Qian Yang, Yi Liu, William Skach, Philip Thomas
Summary: The study reveals an essential role of mammalian RAC in the unfolded protein response (UPR) and its involvement in modulating IRE1 branch activation. RAC is shown to regulate the clustering of IRE1 alpha, which is crucial for endonuclease activation and splicing of Xbp1 mRNA substrate.
Article
Biochemistry & Molecular Biology
Keisuke Yanagida, Kayo Masago, Daisuke Yasuda, Fumie Hamano, Yoshitaka Kurikawa, Takao Shimizu, Satoshi Ishii
Summary: This study examined the functional impacts of amino acid changes in LPA6 identified in ARWH/HT patients. Most mutants failed to respond to LPA and some mutants displayed impaired cell surface expression. The synthetic agonist alkyl-OMPT restored cell surface expression and function of certain mutants.
HUMAN MOLECULAR GENETICS
(2023)
Article
Genetics & Heredity
Udhaya Kotecha, Mehul Mistri, Nidhi Shah, Parth S. Shah, Vandana A. Gupta
Summary: The bi-allelic loss of function mutations in GOLGA2 can cause microcephaly, seizures, and myopathy. This highlights the critical developmental requirement of GOLGA2 and the severe clinical presentation associated with loss of function mutations in affected patients.
Article
Clinical Neurology
Daniel Natera-de Benito, Abel Sola, Paulo Rego Sousa, Susana Boronat, Jessica Exposito-Escudero, Laura Carrera-Garcia, Carlos Ortez, Cristina Jou, Jordi Muchart, Monica Rebollo, Judith Armstrong, Jaume Colomer, Angels Garcia-Cazorla, Janet Hoenicka, Francesc Palau, Andres Nascimento
Summary: The study identified a novel ATP7A mutation in a family with OHS, along with a patient who developed severe worsening of dHMN after copper histidinate treatment. Functional studies showed high levels of superoxide ion in the patient's mitochondria, along with low expression levels of ATP7A and ATP7B.
PEDIATRIC NEUROLOGY
(2021)
Article
Veterinary Sciences
Natielly D. D. Chimenes, Silvana M. M. Caramalac, Simone M. M. Caramalac, Thiago D. D. Fernandes, Roberta M. M. Basso, Fabricio M. Cerri, Jose P. Oliveira-Filho, Alexandre S. S. Borges, Mariana I. P. Palumbo
Summary: This study describes a complex CLCN1 variant in a mixed-breed dog with clinical and electromyographic signs of hereditary myotonia. The variant was found in exon 6, resulting in a premature stop codon in exon 7 and a shortened protein. The myotonic dog was homozygous recessive for the variant, while its parents were heterozygous and its male littermate was homozygous wild-type. Understanding the CLCN1 mutations responsible for hereditary myotonia can provide greater clarity on this condition.
JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION
(2023)
Article
Medicine, General & Internal
Juan Andreu Ansola, Cristina Macia-Rodriguez
Summary: The patient presents with symptoms and history suggestive of an infectious disease, with muscle pain and double vision as the main complaints. After several consultations, it is decided to admit the patient to the internal medicine ward for further clinical investigation focusing on a differential diagnosis of eosinophilia and myopathy.
Article
Clinical Neurology
Meige Liu, Yan Xu, Daojun Hong, Lu Cong, Yangyi Fan, Jun Zhang
Summary: Distal hereditary motor neuropathy (dHMN) is a group of inherited peripheral neuropathies characterized by progressive atrophy and weakness of distal muscle without sensory abnormalities. Next-generation sequencing is an effective diagnostic technique for discovering pathogenic genes in dHMN patients. At least 23 causal genes, including some encoding chaperones, have been identified to be associated with dHMN. This study reports a dHMN patient with a rare DNAJB2 gene variant and neuropathic and myopathic characteristics.
CLINICAL NEUROPATHOLOGY
(2022)
Article
Endocrinology & Metabolism
Shiga Rappai Chirayath, Nisha Bhavani, K. P. Vinayan, V. P. Praveen, Sajitha Nair
Summary: Two critically ill children with rare reversible neurological complications due to DKA showed full recovery after treatment, highlighting the importance of prompt management and multidisciplinary approach in optimizing outcomes.
INTERNATIONAL JOURNAL OF DIABETES IN DEVELOPING COUNTRIES
(2021)
Article
Radiology, Nuclear Medicine & Medical Imaging
Vanessa Vieira, Filipa Sousa, Fabiana Ramos, Elsa Nunes, Miguel Branco
Summary: This study reports the first case of prenatal sonographic finding of bowel dilatation in a fetus with LCHAD deficiency and one of the few cases to report fetal bowel hyperechogenicity.
JOURNAL OF DIAGNOSTIC MEDICAL SONOGRAPHY
(2023)
Review
Cell Biology
Barbara Tedesco, Leen Vendredy, Vincent Timmerman, Angelo Poletti
Summary: Each protein must be correctly synthesized, folded, and transported to its appropriate location. Failure in these steps can lead to protein misfolding and potential damage. Cells have well-characterized protein quality control systems, including autophagy and chaperone-assisted selective autophagy (CASA), to minimize such issues. The CASA complex, composed of HSPA, HSPB8, and BAG3 proteins, is essential for maintaining protein homeostasis and mutations in these genes can result in (cardio)myopathies and neurodegenerative diseases. This article summarizes the current understanding of the CASA complex and discusses its involvement in diseases and potential therapeutic targets.
Article
Clinical Neurology
Jonas Van Lent, Leen Vendredy, Elias Adriaenssens, Tatiana Da Silva Authier, Bob Asselbergh, Marcus Kaji, Sarah Weckhuysen, Ludo van den Bosch, Jonathan Baets, Vincent Timmerman
Summary: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system (PNS), with CMT1A accounting for 40-50% of cases. This study presents an organoid model derived from induced pluripotent stem cells that contains various cell types of the PNS, including myelinating human Schwann cells. They used this model to study disease signatures of CMT1A and found that downregulating PMP22 expression can ameliorate the myelin defects in CMT1A-organoids.
Article
Biochemistry & Molecular Biology
Tetsushi Kataura, Elsje G. Otten, Yoana Rabanal-Ruiz, Elias Adriaenssens, Francesca Urselli, Filippo Scialo, Lanyu Fan, Graham R. Smith, William M. Dawson, Xingxiang Chen, Wyatt W. Yue, Agnieszka K. Bronowska, Bernadette Carroll, Sascha Martens, Michael Lazarou, Viktor Korolchuk
Summary: Mitophagy is essential for maintaining cellular homeostasis. The best characterised pathway involves the stabilisation of PINK1 and recruitment of Parkin to damaged mitochondria. NDP52 recognises ubiquitinated mitochondrial proteins and initiates autophagic vesicle formation. This study found that oxidation of NDP52 is crucial for efficient PINK1/Parkin-dependent mitophagy, and proposed that redox sensing allows mitophagy to function as an oxidative stress response.
Article
Medicine, Research & Experimental
Marta Chierichetti, Mauro Cerretani, Alina Ciammaichella, Valeria Crippa, Paola Rusmini, Veronica Ferrari, Barbara Tedesco, Elena Casarotto, Marta Cozzi, Francesco Mina, Paola Pramaggiore, Mariarita Galbiati, Margherita Piccolella, Alberto Bresciani, Riccardo Cristofani, Angelo Poletti
Summary: The study identified three compounds that can enhance the transcription and translation of HSPB8 and reduce the aggregation propensity of a disease-associated mutant SOD1 protein. These compounds play an important role in improving cellular proteostasis and enhancing selective autophagy, and may have significant clinical implications for treating neurodegenerative diseases and other human disorders.
Article
Clinical Neurology
Mariarita Galbiati, Marco Meroni, Marina Boido, Matilde Cescon, Paola Rusmini, Valeria Crippa, Riccardo Cristofani, Margherita Piccolella, Veronica Ferrari, Barbara Tedesco, Elena Casarotto, Marta Chierichetti, Marta Cozzi, Francesco Mina, Maria Elena Cicardi, Silvia Pedretti, Nico Mitro, Anna Caretto, Patrizia Rise, Angelo Sala, Andrew P. Lieberman, Paolo Bonaldo, Maria Pennuto, Alessandro Vercelli, Angelo Poletti
Summary: Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by motor neuron degeneration, muscle weakness, and an expansion of the CAG triplet repeat in the androgen receptor (AR) gene. In this study, the use of the antiandrogen bicalutamide and the natural disaccharide trehalose showed promising results in ameliorating SBMA pathology in a mouse model. These compounds reduced ARpolyQ toxicity, prevented autophagic flux blockage, and improved muscle morphology and function, suggesting their potential for future clinical trials in SBMA patients.
Article
Clinical Neurology
Giulia Gianferrari, Ilaria Martinelli, Cecilia Simonini, Elisabetta Zucchi, Nicola Fini, Serena Carra, Cristina Moglia, Jessica Mandrioli
Summary: With the increasing importance of personalized approaches based on genetics, it becomes crucial to report new mutations in amyotrophic lateral sclerosis (ALS) genes to better understand their pathogenicity and potential patient responses to specific therapies. SOD1 mutations are the second most common genetic cause of ALS in European populations. In this study, two seemingly unrelated ALS patients from Italy were found to carry the same unfamiliar SOD1 mutation, c.400_402 deletion (p.Glu134del). Both patients exhibited spinal onset, progressive muscular weakness with respiratory involvement, and preserved bulbar function. The possible pathogenic role of this uncommon SOD1 mutation is also discussed.
FRONTIERS IN NEUROLOGY
(2023)
Article
Cell Biology
Barbara Tedesco, Leen Vendredy, Elias Adriaenssens, Marta Cozzi, Bob Asselbergh, Valeria Crippa, Riccardo Cristofani, Paola Rusmini, Veronica Ferrari, Elena Casarotto, Marta Chierichetti, Francesco Mina, Paola Pramaggiore, Mariarita Galbiati, Margherita Piccolella, Jonathan Baets, Femke Baeke, Riet De Rycke, Vincent Mouly, Tommaso Laurenzi, Ivano Eberini, Anna Vihola, Bjarne Udd, Lan Weiss, Virginia Kimonis, Vincent Timmerman, Angelo Poletti
Summary: Chaperone-assisted selective autophagy (CASA) is an important pathway for the disposal of misfolded and aggregating proteins. HSPB8 is a key player in CASA, and recent studies have discovered four novel HSPB8 gene mutations associated with neuromyopathies. These mutations result in the formation of insoluble aggregates and disrupt the proteostasis response, leading to muscle cell dysfunction and impaired sarcomere organization.
Editorial Material
Cell Biology
Simon Alberti, Serena Carra
Summary: The coordination of protein quality control processes across organelles is not well understood. A recent study reveals that the cytosolic juxtanuclear quality control (JUNQ) and intranuclear quality control (INQ) compartments face each other on opposite sides of the nuclear envelope and promote proteostasis before their degradation in vacuoles.
NATURE CELL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Toufic Kassouf, Rohit Shrivastava, Igor Meszka, Aymeric Bailly, Jolanta Polanowska, Helene Trauchessec, Jessica Mandrioli, Serena Carra, Dimitris P. Xirodimas
Summary: The elimination of aberrant inclusions is a potential therapeutic approach for neurodegeneration. In amyotrophic lateral sclerosis (ALS), inhibition of NEDP1 promotes the disassembly of pathological stress granules (SGs) and improves cell survival. Deletion of nedp1 in C. elegans also ameliorates ALS phenotypes related to animal motility. These findings suggest that NEDP1 could be a potential therapeutic target for ALS.
Review
Cell Biology
Heath Ecroyd, Britta Bartelt-Kirbach, Anat Ben-Zvi, Raffaella Bonavita, Yevheniia Bushman, Elena Casarotto, Ciro Cecconi, Wilson Chun Yu Lau, Jonathan D. D. Hibshman, Joep Joosten, Virginia Kimonis, Rachel Klevit, Krzysztof Liberek, Kathryn A. A. McMenimen, Tsukumi Miwa, Axel Mogk, Daniele Montepietra, Carsten Peters, Maria Teresa Rocchetti, Dominik Saman, Angela Sisto, Valentina Secco, Annika Strauch, Hideki Taguchi, Morgan Tanguay, Barbara Tedesco, Melinda E. E. Toth, Zihao Wang, Justin L. P. Benesch, Serena Carra
Summary: The Fourth Cell Stress Society International workshop on small heat shock proteins (sHSPs) was held virtually on November 17-18, 2022, following successful workshops in 2014, 2016, and 2018. The meeting served as a platform for researchers working on sHSPs to reconnect and share their latest findings. The presentations covered a diverse range of topics, reflecting the broad research interests in the field. In this summary, we provide an overview of the presentations and discuss future exciting research directions.
CELL STRESS & CHAPERONES
(2023)