An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models

Prasad, A and Raju, G and Sivalingam, V and Girdhar, A and Verma, M and Vats, A and Taneja, V and G, Prabusankar and Patel, Basant Kumar (2016) An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models. Scientific Reports, 6 (39490). pp. 1-14. ISSN 2045-2322

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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.

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IITH Creators:

IITH Creators	ORCiD
G, Prabusankar	http://orcid.org/0000-0003-1772-135X
Patel, Basant Kumar	http://orcid.org/0000-0001-9465-4803

Item Type:

Article

Additional Information:

We thank Dr. C.S. Sharma & Mr. S. Mattaparthi from Dept. of Chemical Engineering, IIT-Hyderabad and Mr. J. Joseph from Dept. of Electrical Engineering IIT-Hyderabad, for useful help with AFM data acquisition. We also thank Prof. Susan W Liebman, University of Nevada Reno, USA for kindly gifting the yeast strain and plasmids. We also thank IIT-Hyderabad funded by MHRD, Govt. of India, for research infrastructure & support.

Subjects:

Others > Biotechnology
Chemistry

Divisions:

Department of Biotechnology
Department of Chemistry

Depositing User:

Team Library

Date Deposited:

28 Dec 2016 05:06

Last Modified:

12 Sep 2017 06:20

URI:

http://raiithold.iith.ac.in/id/eprint/2940