Article
Multidisciplinary Sciences
Anny Devoy, Georgia Price, Francesca De Giorgio, Rosie Bunton-Stasyshyn, David Thompson, Samanta Gasco, Alasdair Allan, Gemma F. Codner, Remya R. Nair, Charlotte Tibbit, Ross McLeod, Zeinab Ali, Judith Noda, Alessandro Marrero-Gagliardi, Jose M. Brito-Armas, Muhammet M. Ozturk, Michelle Simon, Edward O'Neill, Sam Bryce-Smith, Jackie Harrison, Gemma Atkins, Silvia Corrochano, Michelle Stewart, Lydia Teboul, Abraham Acevedo-Arozena, Elizabeth M. C. Fisher, Thomas J. Cunningham
Summary: The study team has created next-generation genomically humanized knockin mouse models for improved understanding and therapeutic development of Amyotrophic lateral sclerosis/frontotemporal dementia. Extensive analysis and characterization of humanized mice demonstrated their normal phenotype and potential for preclinical assessment and disease mechanism research.
Article
Clinical Neurology
Sara Salvany, Anna Casanovas, Lidia Piedrafita, Silvia Gras, Jordi Caldero, Josep E. Esquerda
Summary: Early misfolded superoxide dismutase 1 (mfSOD1) accumulation, motor neuron (MN) degeneration, and microgliosis are hallmark pathological features in SOD1(G93A) amyotrophic lateral sclerosis (ALS) mice. Different MN subtypes exhibit varying vulnerabilities, leading to the coexistence of degenerating and surviving MNs during disease progression. The most severe phenotype is observed in fast-twitch subtype MNs, which display high levels of mfSOD1 and extensive vacuolar degeneration. Vacuoles, originating from mitochondria, contain mfSOD1 along with nonmitochondrial proteins. The fusion of ER-derived vesicles enriched with mfSOD1 and outer mitochondrial membranes is believed to be the main mechanism for vacuole formation. Vacuolar degeneration occurs transiently in the presymptomatic stages of ALS, and vacuolated MNs also express the effector protein pMLKL, suggesting a mechanism involving extracellular vesicles in neuroinflammation and disease spreading. Additionally, the expression of mfSOD1 and local neuroinflammation demonstrate bidirectional communication, as manipulation of microglial response affects MN phenotypes. Detailed understanding of these processes prior to the end stages of the disease is essential for identifying novel therapeutic targets.
Article
Medicine, General & Internal
Wen-Chao Liu, Na Liu, Yan Wang, Chen Huang, Yan-Fang Li, Hao Wang, Xiao-Gang Li, Min Deng
Summary: Research shows that motor neurons (MNs) derived from ALS patient-specific iPSC lines can replicate key aspects of ALS pathogenesis, providing insights into the disease's pathophysiological processes. Incremental mutant expressions of SOD1 in MNs may disrupt cellular function, leading to intracellular calcium disturbances and contributing to the onset of the disease.
CHINESE MEDICAL JOURNAL
(2021)
Article
Cell Biology
Chaohua Cong, Weiwei Liang, Chunting Zhang, Ying Wang, Yueqing Yang, Xudong Wang, Shuyu Wang, Di Huo, Hongyong Wang, Di Wang, Honglin Feng
Summary: In ALS models, the expression and activation of PAK4 significantly decreased as the disease progressed due to the negative regulation of miR-9-5p. Silencing PAK4 increased apoptosis of motor neurons by inhibiting CREB-mediated neuroprotection, while overexpression of PAK4 protected motor neurons from degeneration by activating CREB signaling.
CELL PROLIFERATION
(2021)
Article
Biochemistry & Molecular Biology
Jose R. Monteiro Neto, Gabriela D. Ribeiro, Rayne S. S. Magalhaes, Cristian Follmer, Tiago F. Outeiro, Elis C. A. Eleutherio
Summary: This study found a relationship between the formation of methylglyoxal (MGO) and the degeneration of motor neurons in Amyotrophic Lateral Sclerosis (ALS). The accumulation of MGO led to the aggregation of human SOD1WT (hSOD1WT), decreased activity, and reduced cell viability. Additionally, MGO treatment increased the presence of hSOD1WT in stress granules. These findings suggest that glycation may play a significant role in the pathologies of hSOD1WT and TDP-43 in sporadic ALS.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Review
Clinical Neurology
Lu Xu, Bingjie He, Yunjing Zhang, Lu Chen, Dongsheng Fan, Siyan Zhan, Shengfeng Wang
Summary: This study reviewed prognostic models for ALS and found methodological pitfalls and lack of external validation by fully independent researchers. Future research should focus on adding novel predictors, external validation, and head-to-head comparisons of existing models.
JOURNAL OF NEUROLOGY
(2021)
Article
Clinical Neurology
Abrar Alhindi, Megan Shand, Hannah L. Smith, Ana S. Leite, Yu-Ting Huang, Dinja van Der Hoorn, Zara Ridgway, Kiterie M. E. Faller, Ross A. Jones, Thomas H. Gillingwater, Helena Chaytow
Summary: This study comprehensively analyzed the neuromuscular junction pathology in a mouse model of ALS. The results showed progressive, region-specific motor neuron pathology in Thy1-hTDP-43(WT) mice. The loss of terminal Schwann cells was directly correlated with motor neuron denervation.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2023)
Review
Neurosciences
Elizabeth M. C. Fisher, Linda Greensmith, Andrea Malaspina, Pietro Fratta, Michael G. Hanna, Giampietro Schiavo, Adrian M. Isaacs, Richard W. Orrell, Thomas J. Cunningham, Abraham Acevedo Arozena
Summary: Amyotrophic lateral sclerosis (ALS) is a complex disorder with mostly unknown cause, but around 10% of cases are familial and caused by mutations in over 30 different genes. Mouse models exist for many genetic forms of ALS, but there is currently no model for the majority of ALS cases that are sporadic. The development of potential therapies has primarily relied on limited mouse models and has been tested on patients with different etiologies. The use of complex mouse models and patient stratification in clinical trials has proven successful in cancer research, and adopting a similar approach could lead to better understanding of ALS pathologies and faster translation of research findings into effective therapies.
MOLECULAR NEURODEGENERATION
(2023)
Article
Pharmacology & Pharmacy
Elias Marlin, Miguel Valencia, Nuria Peregrin, Roberto Ferrero, Maria Jesus Nicolas, Rodrigo Vinueza-Gavilanes, Antonio Pineda-Lucena, Julio Artieda, Montserrat Arrasate, Tomas Aragon
Summary: In this study, two eIF2B activators, 2BAct and PRXS571, were found to anticipate disease onset in SOD1G93A mice, exacerbating muscle denervation and motor neuronal death. The compounds relieved translational inhibition imposed by ISR while maintaining high ATF4 levels in primary neurons. The findings suggest that ISR may function as a neuroprotective pathway in ALS motor neurons, but caution on the potential toxicity of eIF2B activators in ALS patients.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Clinical Neurology
Juan F. Vazquez-Costa, Daniel Borrego-Hernandez, Carmen Paradas, Maria Teresa Gomez-Caravaca, Ricardo Rojas-Garcia, Luis Varona, Monica Povedano, Tania Garcia-Sobrino, Ivonne Jerico Pascual, Antonio Gutierrez, Javier Riancho, Janina Turon-Sans, Abdelilah Assialioui, Jordi Perez-Tur, Teresa Sevilla, Jesus Esteban Perez, Alberto Garcia-Redondo
Summary: This study investigated the frequency and distribution of SOD1 mutations in ALS patients in Spain. It found 29 mutations, including 7 novel mutations, in all five exons of SOD1. The frequency of these mutations varied among regions. Older age of onset and female sex were associated with faster disease progression and poorer survival.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Food Science & Technology
Salvatore D'Antona, Martina Caramenti, Danilo Porro, Isabella Castiglioni, Claudia Cava
Summary: Amyotrophic lateral sclerosis (ALS) is a fatal disease linked to motor neurons degeneration, with diet components like oxidative stress potentially influencing its onset. Some diets with antioxidant and anti-inflammatory properties may reduce the risk of ALS, but current data remains controversial.
Article
Cell Biology
Seung-Hye Choi, Ali Yousefian-Jazi, Seung Jae Hyeon, Phuong Thi Thanh Nguyen, Jiyeon Chu, Sojung Kim, Suhyun Kim, Hannah L. Ryu, Neil W. Kowall, Hoon Ryu, Junghee Lee
Summary: In this study, researchers found that modulating the activity of LSD1 can improve the neuropathology of ALS mice, delay disease onset, and extend lifespan, potentially serving as an effective therapeutic strategy for treating ALS.
JOURNAL OF BIOMEDICAL SCIENCE
(2022)
Article
Neurosciences
Albert J. B. Lee, Tyler E. E. Kittel, Renaid B. B. Kim, Thao-Nguyen Bach, Tian Zhang, Cassie S. S. Mitchell
Summary: The study aimed to determine the most beneficial pathophysiological treatment targets for ALS. The results showed that treatments targeting inflammation were best at delaying disease onset, oxidative stress treatments significantly prolonged survival, and excitability treatments improved overall health status. The best pathophysiological treatment category varied with disease progression and combination treatments targeting multiple categories performed better than monotherapies at end-stage.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Clinical Neurology
Sara Hernandez, Sara Salvany, Anna Casanovas, Lidia Piedrafita, M. Clara Soto-Bernardini, Olga Tarabal, Alba Blasco, Silvia Gras, Alao Gatius, Markus H. Schwab, Jordi Caldero, Josep E. Esquerda
Summary: This article investigates the therapeutic impact of neuregulin-1 (NRG1) on amyotrophic lateral sclerosis (ALS). Using a transgenic mouse model, the study finds that enhanced NRG1 signaling does not significantly improve the pathological features of SOD1-induced disease, but instead accelerates disease onset and worsens motor phenotype.
Article
Clinical Neurology
Giammarco Milella, Stefano Zoccolella, Alessia Giugno, Marco Filardi, Daniele Urso, Salvatore Nigro, Benedetta Tafuri, Ludovica Tamburrino, Valentina Gnoni, Giancarlo Logroscino
Summary: This study found that spinal-onset ALS can be categorized into three groups based on the extent of upper motor neuron (UMN) and lower motor neuron (LMN) involvement. UMN burden is associated with higher diagnostic certainty and broader disease spread, while LMN involvement is associated with more severe disease and shorter survival.
JOURNAL OF NEUROLOGY
(2023)
Review
Neurosciences
Alessia Loffreda, Monica Nizzardo, Alessandro Arosio, Marc-David Ruepp, Raffaele A. Calogero, Stefano Volinia, Marco Galasso, Caterina Bendotti, Carlo Ferrarese, Christian Lunetta, Mafalda Rizzuti, Antonella E. Ronchi, Oliver Muhlemann, Lucio Tremolizzo, Stefania Corti, Silvia M. L. Barabino
PROGRESS IN NEUROBIOLOGY
(2020)
Article
Cell Biology
Marco Ceccanti, Valeria Pozzilli, Chiara Cambieri, Laura Libonati, Emanuela Onesti, Vittorio Frasca, Ilenia Fiorini, Antonio Petrucci, Matteo Garibaldi, Eleonora Palma, Caterina Bendotti, Paola Fabbrizio, Maria Chiara Trolese, Giovanni Nardo, Maurizio Inghilleri
Review
Clinical Neurology
Caterina Bendotti, Valentina Bonetto, Elisabetta Pupillo, Giancarlo Logroscino, Ammar Al-Chalabi, Christian Lunetta, Nilo Riva, Gabriela Mora, Giuseppe Lauria, Jochen H. Weishaupt, Federica Agosta, Andrea Malaspina, Manuela Basso, Linda Greensmith, Ludo van den Bosch, Antonia Ratti, Massimo Corbo, Orla Hardiman, Adriano Chio, Vincenzo Silani, Ettore Beghi
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
(2020)
Review
Biochemistry & Molecular Biology
Giada Cipollina, Arash Davari Serej, Gianluca Di Nolfi, Andrea Gazzano, Andrea Marsala, Mauro G. Spatafora, Marco Peviani
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)
Article
Multidisciplinary Sciences
Marco Peviani, Giorgia Spano, Antonella Pagani, Gianluca Brugnara, Cesare Covino, Rossella Galli, Alessandra Biffi, Letterio S. Politi
SCIENTIFIC REPORTS
(2020)
Article
Medicine, General & Internal
Maria Chiara Trolese, Alessandro Mariani, Mineko Terao, Massimiliano de Paola, Paola Fabbrizio, Francesca Sironi, Mami Kurosaki, Silvia Bonanno, Silvia Marcuzzo, Pia Bernasconi, Francesca Trojsi, Eleonora Aronica, Caterina Bendotti, Giovanni Nardo
Article
Chemistry, Multidisciplinary
Renato Auriemma, Mattia Sponchioni, Umberto Capasso Palmiero, Giacomo Rossino, Arianna Rossetti, Andrea Marsala, Simona Collina, Alessandro Sacchetti, Davide Moscatelli, Marco Peviani
Summary: Reactive microgliosis is a prevalent pathological feature in various neurodegenerative diseases, and positron emission tomography (PET) using TSPO ligands like PBR28 has emerged as a valuable strategy to assess and monitor microgliosis. A synthetic pathway for a PBR28 derivative, PBR-alkyne, was explored to enable selective targeting of TSPO-expressing cells, demonstrating efficient internalization in cultured microglia-like cell lines when decorated on zwitterionic biodegradable polymer nanoparticles.
Article
Biochemistry & Molecular Biology
Savina Apolloni, Paola Fabbrizio, Susanna Amadio, Giulia Napoli, Mattia Freschi, Francesca Sironi, Paolo Pevarello, Paola Tarroni, Chiara Liberati, Caterina Bendotti, Cinzia Volonte
Summary: Amyotrophic lateral sclerosis (ALS) is a neuroinflammatory disease where the role of P2X7 receptor has been highlighted, and the novel P2X7 antagonist AXX71 shows potential therapeutic value in ALS by targeting microglia-related proinflammatory markers and autophagy during the early symptomatic phase of the disease. This suggests that P2X7 modulation could be further explored as a therapeutic strategy in preclinical studies and applied in ALS clinical trials.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Giacomo Rossino, Marta Rui, Pasquale Linciano, Daniela Rossi, Massimo Boiocchi, Marco Peviani, Elena Poggio, Daniela Curti, Dirk Schepmann, Bernhard Wuensch, Mariela Gonzalez-Avendano, Ariela Vergara-Jaque, Julio Caballero, Simona Collina
Summary: A novel series of bitopic S1R ligands were developed, with compound 7 showing low nanomolar affinity and potential to stabilize the open conformation of S1R. Computational analyses suggest that these findings pave the way for new S1R ligands with enhanced activity and the identification of allosteric sites.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Geriatrics & Gerontology
Andrea David Re Cecconi, Mara Barone, Simona Gaspari, Massimo Tortarolo, Caterina Bendotti, Luca Porcu, Giulia Terribile, Rosanna Piccirillo
Summary: Cancer cachexia and ALS seem to have similar mechanisms of muscle wasting at least at the catabolic level. The p97-Nploc4 complex appears to play a crucial role in muscle atrophy during these disorders, and disrupting this complex might serve as a novel drug strategy.
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE
(2022)
Article
Clinical Neurology
Ettore Beghi, Elisabetta Pupillo, Elisa Bianchi, Valentina Bonetto, Silvia Luotti, Laura Pasetto, Caterina Bendotti, Massimo Tortarolo, Francesca Sironi, Laura Camporeale, Alexander V. Sherman, Sabrina Paganoni, Ada Scognamiglio, Fabiola De Marchi, Paolo Bongioanni, Renata Del Carratore, Claudia Caponnetto, Luca Diamanti, Daniele Martinelli, Andrea Calvo, Massimiliano Filosto, Alessandro Padovani, Stefano Cotti Piccinelli, Claudia Ricci, Stefania Dalla Giacoma, Nicoletta De Angelis, Maurizio Inghilleri, Rossella Spataro, Vincenzo La Bella, Giancarlo Logroscino, Christian Lunetta, Claudia Tarlarini, Jessica Mandrioli, Ilaria Martinelli, Cecilia Simonini, Elisabetta Zucchi, Maria Rosaria Monsurro, Dario Ricciardi, Francesca Trojsi, Nilo Riva, Massimo Filippi, Isabella Laura Simone, Gianni Soraru, Cristina Spera, Lucia Florio, Sonia Messina, Massimo Russo, Gabriele Siciliano, Amelia Conte, Maria Valeria Saddi, Nicola Carboni, Letizia Mazzini
Summary: This study is a clinical trial on the effects of RNS60 in ALS patients. The results indicate that RNS60 has positive effects on respiratory and bulbar function, suggesting further investigation is warranted.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Neurosciences
Francesca Sironi, Fabiola De Marchi, Letizia Mazzini, Caterina Bendotti
Summary: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons and neuromuscular impairment. Stem cell therapy shows promise in protecting motor units through various mechanisms. However, more coordinated effort and research is needed to address challenges in stem cell source selection, mechanism of action, and expected clinical outcomes. This review covers recent advances in stem cell therapies in ALS animal models and ongoing human clinical trials.
BRAIN RESEARCH BULLETIN
(2023)
Article
Medicine, Research & Experimental
Marco Peviani, Sabyasachi Das, Janki Patel, Odella Jno-Charles, Rajesh Kumar, Ana Zguro, Tyler D. Mathews, Paolo Cabras, Rita Milazzo, Eleonora Cavalca, Valentina Poletti, Alessandra Biffi
Summary: Hematopoietic stem and progenitor cells (HSPCs) can be used to treat the severe CLN1 neurodegenerative disorder, and the transplantation of HSPCs over-expressing hPPT1 enhances the therapeutic benefit. This novel approach shows promise for treating CLN1 disease and other neurodegenerative conditions.
EMBO MOLECULAR MEDICINE
(2023)
Article
Cell Biology
Paola Fabbrizio, Cassandra Margotta, Jessica D'Agostino, Giuseppe Suanno, Lorenzo Quetti, Caterina Bendotti, Giovanni Nardo
Summary: Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease with a poor prognosis and unmet therapeutic need. Recent research suggests that the modulation of macrophage muscle response and enhancement of satellite cell differentiation can delay muscle atrophy and motor neuron loss in ALS. IL-10 treatment was found to improve motor performance in ALS mice by promoting satellite cells and muscle pro-regenerative activity of macrophages.
Article
Biochemistry & Molecular Biology
Antonio Vallarola, Massimo Tortarolo, Roberta De Gioia, Luisa Iamele, Hugo de Jonge, Giovanni de Nola, Enrica Bovio, Laura Pasetto, Valentina Bonetto, Mattia Freschi, Caterina Bendotti, Ermanno Gherardi
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)