title: An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with aggregation of TAR DNA-binding protein-43 (TDP-43) in neuronal cells and manifests as motor neuron dysfunction &muscle atrophy. The carboxyl-terminal prion-like domain of TDP-43 can aggregate in vitro into toxic β-sheet rich amyloid-like structures. So far, treatment options for ALS are very limited and Riluzole, which targets glutamate receptors, is the only but highly ineffective drug. Therefore, great interest exists in developing molecules for ALS treatment. Here, we have examined certain derivatives of acridine containing same side chains at position 4 &5, for inhibitory potential against TDP-43 aggregation. Among several acridine derivatives examined, AIM4, which contains polar carboxyl groups in the side arms, significantly reduces TDP-43-YFP aggregation in the powerful yeast model cell and also abolishes in vitro amyloid-like aggregation of carboxyl terminal domain of TDP-43, as observed by AFM imaging. Thus, AIM4 can be a lead molecule potentiating further therapeutic research for ALS.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Medak Dist, Telangana, 502285, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Prasad
authors.affiliation: Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Medak Dist, Telangana, 502285, India.
authors.forename: Gembali
authors.initials: G
authors.lastname: Raju
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Medak Dist, Telangana, 502285, India.
authors.forename: Vishwanath
authors.initials: V
authors.lastname: Sivalingam
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Medak Dist, Telangana, 502285, India.
authors.forename: Amandeep
authors.initials: A
authors.lastname: Girdhar
authors.affiliation: Genomics and Molecular Medicine, CSIR-Institute of Genomics &Integrative Biology, Mall Road, New Delhi, 110007, India.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Verma
authors.affiliation: Department of Research, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110060, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Vats
authors.affiliation: Department of Research, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110060, India.
authors.forename: Vibha
authors.initials: V
authors.lastname: Taneja
authors.affiliation: Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Medak Dist, Telangana, 502285, India.
authors.forename: Ganesan
authors.initials: G
authors.lastname: Prabusankar
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Medak Dist, Telangana, 502285, India.
authors.forename: Basant K
authors.initials: BK
authors.lastname: Patel
mesh_terms: D000166:Acridines / Q000737:chemistry*; D000682:Amyloid / Q000737:chemistry; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D001965:Bromides / Q000737:chemistry*; D002942:Circular Dichroism; D004268:DNA-Binding Proteins / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D008856:Microscopy, Fluorescence; D009046:Motor Neurons / Q000473:pathology; D009133:Muscular Atrophy / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D011328:Prions / Q000737:chemistry; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000166:Acridines; D000682:Amyloid; D001965:Bromides; D004268:DNA-Binding Proteins; D007093:Imidazoles; D011328:Prions; D011994:Recombinant Proteins; C000598624:TARDBP protein, human