Article
Biochemistry & Molecular Biology
Julia Smirnova, Julia Gavrilova, Andra Noormagi, Karin Valmsen, Hegne Pupart, Jinghui Luo, Vello Tougu, Peep Palumaa
Summary: The demetallation of Cu,Zn-SOD1 and its G93A mutant was investigated in the presence of different metal ion chelators at varying temperatures. The results showed that both Zn2+ and Cu2+ were released simultaneously from the protein at elevated temperatures, and the release rate depended on the concentration of chelating ligands but was almost independent of their metal-binding affinities. The demetallation of Cu,Zn-SOD1 always came to completion, hinderinng the calculation of the K-D values. The high Delta H values indicated protein conformational changes before demetallation, suggesting that Cu,Zn-SOD1 complex is kinetically inert in native conditions. The fibrillization of both forms of SOD1 was similar.
Article
Chemistry, Multidisciplinary
Ahmet Can Timucin, Suleyman Selim Cinaroglu, Osman Ugur Sezerman, Emel Timucin
Summary: The metallation status of human Cu/Zn superoxide dismutase 1 (SOD1) is crucial in the development of amyotrophic lateral sclerosis (ALS). Mutations at the ALS-linked positions H63R and K136A significantly affect dimer dynamics, leading to demetallation and potential ALS toxicity. This study highlights the potential use of atomistic simulations in studying disease variants related to SOD1.
FRONTIERS IN CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Lassi Koski, Cecilia Ronnevi, Elina Berntsson, Sebastian K. T. S. Warmlander, Per M. Roos
Summary: ALS, Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders have a significant impact on patients, caregivers, and society due to the aggregation of proteins in nerve cells. TDP-43 seems to play a specific role in ALS pathogenesis, and further research is needed on the role of metals in TDP-43 aggregation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biology
Yeongjin Baek, Tae-Gyun Woo, Jinsook Ahn, Dukwon Lee, Yonghoon Kwon, Bum-Joon Park, Nam-Chul Ha
Summary: This study explored the molecular mechanism of SOD1 filament formation in sALS and found that overoxidized SOD1 is a triggering factor of sALS. Our findings extend our understanding of other neurodegenerative disorders associated with ROS stresses at the molecular level.
COMMUNICATIONS BIOLOGY
(2022)
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
Neurosciences
Serenella Anzilotti, Valeria Valsecchi, Paola Brancaccio, Natascia Guida, Giusy Laudati, Valentina Tedeschi, Tiziana Petrozziello, Francesco Frecentese, Elisa Magli, Brenda Hassler, Ornella Cuomo, Luigi Formisano, Agnese Secondo, Lucio Annunziato, Giuseppe Pignataro
Summary: NCX1 and NCX2 play a significant role in the pathophysiology of ALS, and pharmacological activation with neurounina can improve the pathological features of ALS mice, extending lifespan and alleviating motor symptoms.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Anna Shteinfer-Kuzmine, Shirel Argueti-Ostrovsky, Marcel F. Leyton-Jaimes, Uttpal Anand, Salah Abu-Hamad, Ran Zalk, Varda Shoshan-Barmatz, Adrian Israelson
Summary: This study suggests that the interaction between VDAC1 and SOD1 is involved in the pathogenesis of ALS. By inhibiting VDAC1 oligomerization, it is possible to reduce cell apoptosis and related processes caused by mutant SOD1, thus improving muscle function in ALS patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Immunology
Yuan Chao Xue, Huitao Liu, Yasir Mohamud, Amirhossein Bahreyni, Jingchun Zhang, Neil R. Cashman, Honglin Luo
Summary: This study identifies CVB3 infection as a risk factor for early onset and accelerated progression of ALS, provides evidence for the potential association between the virus and ALS, and discovers that early administration of ribavirin can rescue ALS-like pathology and symptoms induced by CVB3 infection.
JOURNAL OF NEUROINFLAMMATION
(2022)
Article
Clinical Neurology
Teuta Domi, Paride Schito, Giacomo Sferruzza, Tommaso Russo, Laura Pozzi, Federica Agosta, Paola Carrera, Nilo Riva, Massimo Filippi, Angelo Quattrini, Yuri Matteo Falzone
Summary: This study aims to outline the clinical features of SOD1-ALS patients by comparing them to patients without ALS major gene variants and patients with variants in other major ALS genes. Defining the SOD1-ALS phenotype can assist clinicians in identifying patients who should be prioritized for genetic testing.
JOURNAL OF NEUROLOGY
(2023)
Article
Cell Biology
Joke De Vocht, Donatienne Van Weehaeghe, Fouke Ombelet, Pegah Masrori, Nikita Lamaire, Martijn Devrome, Hilde Van Esch, Mathieu Moisse, Michel Koole, Patrick Dupont, Koen Van Laere, Philip Van Damme
Summary: This study examined the impact of ALS-causing gene mutations on cerebral glucose metabolism using genetic testing and FDG PET imaging. The results showed distinctive differences in glucose metabolism patterns between C9orf72-ALS patients and sporadic ALS patients, particularly in specific regions of the brain.
Article
Cell Biology
Andrea Magri, Cristiana Lucia Rita Lipari, Pierpaolo Risiglione, Stefania Zimbone, Francesca Guarino, Antonella Caccamo, Angela Messina
Summary: Mitochondrial dysfunction and impaired mitophagy contribute to the onset of ALS. We found that reduced mitochondrial respiration, driven by complex I and II inhibition, is correlated with ALS motor symptoms. Additionally, we observed increased levels of TSPO and decreased expression of Atg12, suggesting impairments in mitophagy activation.
CELL DEATH & DISEASE
(2023)
Article
Neurosciences
Daehwan Kim, Subin Kim, Ashley Sung, Neetika Patel, Nathan Wong, Michael J. Conboy, Irina M. Conboy
Summary: The research demonstrates that the conditioned medium from ALS patient-derived induced pluripotent stem cells (iPSCs) has significant neuroprotective effects, attenuates various aspects of ALS pathology, improves neuro-muscular health, and delays paralysis and disease progression. Mitochondrial stabilization and downregulation of inflammatory genes may contribute to the neuroprotective mechanism of the iPSC-conditioned medium.
TRANSLATIONAL NEURODEGENERATION
(2022)
Article
Cell Biology
Maria Garofalo, Cecilia Pandini, Matteo Bordoni, Emanuela Jacchetti, Luca Diamanti, Stephana Carelli, Manuela Teresa Raimondi, Daisy Sproviero, Valeria Crippa, Serena Carra, Angelo Poletti, Orietta Pansarasa, Stella Gagliardi, Cristina Cereda
Summary: This study conducted gene expression analysis on sporadic ALS patients and healthy controls, and found that patients with high and low levels of nSOD1 have different gene expression patterns. High-nSOD1 patients activate pathways related to upregulation of HSP70 molecular chaperones, leading to reduced DNA damage under oxidative stress conditions.
Article
Biochemistry & Molecular Biology
Natalia Nowicka, Kamila Szymanska, Judyta Juranek, Kamila Zglejc-Waszak, Agnieszka Korytko, Michal Zalecki, Malgorzata Chmielewska-Krzesinska, Krzysztof Wasowicz, Joanna Wojtkiewicz
Summary: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unclear pathogenesis. RAGE and its ligands have been found to play an important role in the pathogenesis of ALS.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Agnes Badu-Mensah, Xiufang Guo, Roxana Mendez, Hemant Parsaud, James J. Hickman
Summary: Research indicates that improving muscle function can enhance neuromuscular junction integrity and reduce fatigue in amyotrophic lateral sclerosis (ALS). This study suggests that muscle could be a therapeutic target in ALS drug discovery and emphasizes the importance of considering all tissues involved in multi-systemic diseases. It also establishes a platform for mutation-specific drug screening, which could lead to personalized medicine for rare diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biology
E. Srinivasan, Nandhini Natarajan, R. Rajasekaran
COMPUTATIONAL BIOLOGY AND CHEMISTRY
(2020)
Review
Biochemistry & Molecular Biology
E. Srinivasan, R. Rajasekaran
JOURNAL OF MOLECULAR NEUROSCIENCE
(2020)
Article
Biochemistry & Molecular Biology
P. Chandra Sekar, R. Rajasekaran
Summary: The study examined the competitive inhibitor activity of a broad spectrum antimicrobial peptide, Dermaseptin-S4 (S4) and its analogues, revealing that S4 (K-4) established more inter-molecular interactions compared to S4 (K4K20) and S1-ACE2. The normal mode analysis (NMA) showed that the S1-S4 (K-4) complex exhibited higher energy deformation profile and conformational transition, suggesting its potential as the best therapeutic scaffold to block SARS-CoV-2 infection.
INTERNATIONAL JOURNAL OF PEPTIDE RESEARCH AND THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
P. Chandra Sekar, D. Meshach Paul, E. Srinivasan, R. Rajasekaran
Summary: Ocellatin AMPs are considered as promising alternatives to conventional antibiotics, with ocellatin-1 peptide showing strong membrane permeability and potential therapeutic efficacy. Computational analyses indicated non-toxicity and membrane-permeable efficacy of ocellatin-1, making it a suitable scaffold for therapeutics. Trajectory analysis further revealed strong structural stability and important role in bacterial membrane penetration, highlighting the therapeutic potential of ocellatin-1 as an antimicrobial drug.
JOURNAL OF MOLECULAR MODELING
(2021)
Article
Biochemistry & Molecular Biology
G. Chandrasekhar, R. Rajasekaran
Summary: In humans, cystatin C mediated amyloid aggregation is harmful, but targeting the protein at the initial pathogenic stage with peptide therapy, specifically the 'LVN' tripeptide, could effectively reduce the aggregation and pathogenic behavior of cystatin C amyloidosis.
INTERNATIONAL JOURNAL OF PEPTIDE RESEARCH AND THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
P. Chandra Sekar, G. Chandrasekhar, R. Rajasekaran
Summary: Antimicrobial peptides (AMPs) are evolutionarily conserved components of the innate immune system found in all living organisms. Due to their relatively lower microbial drug resistance, AMPs can serve as efficient small molecule drugs. Ocellatin-1 (O1) AMP from the South American frog Leptodactylus ocellatus shows greater efficacy against pathogens due to its unique amino acid residues contributing to its structural stability and functional activity. By analyzing the key residues in O1 AMP, it was found that specific residues like isoleucine and leucine are crucial for maintaining its therapeutic scaffold. Additionally, molecular simulation and computational analysis further confirmed the importance of these residues in O1 AMP for potential drug discovery applications.
INTERNATIONAL JOURNAL OF PEPTIDE RESEARCH AND THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
G. Chandrasekhar, P. Chandra Sekar, E. Srinivasan, A. Amarnath, H. Pengyong, R. Rajasekaran
Summary: The study quantitatively analyzed and investigated the effects of single nucleotide polymorphisms (SNPs) occurring in the 170-178 mutation hotspot site of APoA1 on biomolecular modifications. Results from discrete molecular dynamics simulation studies showed that SNPs significantly altered the behavior of ApoA1 from its native structural dynamics. Analysis of secondary structural changes in the protein revealed considerable alterations post mutations. Additionally, simulated thermal denaturation of the protein structures showed increased resistance to denaturation among mutants compared to native. Further, normal mode analysis of protein's dynamic motion exhibited discrepancies in dynamic structural changes induced by SNPs, which could play a role in driving ApoA1 into its amyloidogenesis.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Biochemical Research Methods
G. Chandrasekhar, E. Srinivasan, P. Chandra Sekar, S. Venkataramanan, R. Rajasekaran
Summary: The study investigates the subversive nature of point mutation in TTR promoting amyloidogenicity using DMD simulations, and suggests the potential of resveratrol in mitigating the pathogenic repercussions of mutant TTR as an aid towards structure-based drug design in the research on familial amyloid disorders.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2022)
Article
Chemistry, Multidisciplinary
E. Srinivasan, G. Chandrasekhar, P. Chandrasekar, K. Anbarasu, A. S. Vickram, Iftikhar Aslam Tayubi, R. Rajasekaran, Rohini Karunakaran
Summary: Protein misfolding leads to the formation of amyloid fibrils associated with neurodegenerative diseases like Alzheimer's disease. Herbal compounds have been identified as potential inhibitors of A beta 42 fibrils, offering a promising approach for AD treatment.
FRONTIERS IN CHEMISTRY
(2021)
Review
Medicine, General & Internal
E. Srinivasan, G. Chandrasekhar, P. Chandrasekar, K. Anbarasu, A. S. Vickram, Rohini Karunakaran, R. Rajasekaran, P. S. Srikumar
Summary: Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons, with pathogenesis linked to the misfolding and mutations of alpha-synuclein protein. Genetic and other factors lead to the formation of amyloid structures from alpha-synuclein, causing PD.
FRONTIERS IN MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
P. Chandra Sekar, E. Srinivasan, G. Chandrasekhar, D. Meshach Paul, G. Sanjay, S. Surya, N. S. Arun Raj Kumar, R. Rajasekaran
Summary: This study compared the intermolecular interactions between the SARS-CoV-2 spike protein S1 and alpha helical AMPs extracted from frog skin, and found that the Spike-Dermaseptin-S9 complex had more interactions. Molecular dynamics and conformational sampling analysis showed that Dermaseptin-S9 can alter the conformation of S1 and maintain high structural stability. Therefore, Dermaseptin-S9 could be a strong candidate for preventing SARS-CoV-2 infection.
JOURNAL OF MOLECULAR MODELING
(2022)
Article
Biotechnology & Applied Microbiology
G. Chandrasekhar, H. Pengyong, G. Pravallika, L. Hailei, X. Caixia, R. Rajasekaran
Summary: The study aimed to develop a therapeutic candidate to inhibit the pathogenic misfolding of V30M mutant transthyretin (TTR) protein. The antimicrobial peptide NaD1 was chosen due to its aggregating ability, which could compete with the aggregation-prone regions of TTR protein. Two NaD1-derived tetra peptides, CKTE and SKIL, were proposed as initial candidates based on their association with mutant TTR protein. The CKTE tetra peptide showed significant interaction and therapeutic potential in disrupting the beta-sheets and aggregation of V30M TTR protein.
Article
Chemistry, Multidisciplinary
Paul D. D. Meshach, Chandrasekhar Gopalakrishnan, Chandra Sekar Ponnusamy, Udhaya Lavinya, Rajasekaran Ramalingam
Summary: Fabry disease (FD) is a rare genetic disorder caused by the deficiency of the alpha-galactosidase enzyme, resulting in the accumulation of globotriaosylceramide fat. Despite the lack of effective therapeutics, 1-deoxygalactonojirimycin (DGJ) has shown promise as a pharmacological chaperone for alpha-Gal mutants. This study investigates the theoretical details of DGJ's ability to improve the functional activity of specific alpha-Gal mutants through structural and dynamic analysis.