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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal disease associated with motor neuron degeneration and far, there is no cure or effective treatment for ALS7
These compounds have two methylimidazolium groups at the C-4 and C-5 positions of the planar acridine skeleton and differ in the side chains attached to the imidazolium and in the counter anions associated with the positive charge on the imidazolium groups[37]
An anti-amyloid drug tafamidis, which acts by arresting the aggregating protein transthyretin into normally folded tetrameric form, has been shown to slow disease progression which has led to its FDA-approval for treatment of transthyretin amyloidosis[49,50]
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal disease associated with motor neuron degeneration and far, there is no cure or effective treatment for ALS7. Imidazolium groups were linked with side chains such as isopropyl, ester or carboxylic acid, which display varying hydrophilicity to impart differential interaction capability with biomolecules Another derivative of acridine, 4,5-bis(hydroxymethyl)acridine, which lacks imidazole in the side arms but contains polar hydroxymethyl groups at carbon 4 & 5 of acridine, was examined for anti-aggregation ability against TDP-43. The effect of these compounds on in vitro aggregation of TDP-43’s C-terminal amyloidogenic fragment (TDP-432C), using tools like ThT fluorescence, circular dichroism, and AFM37. We have examined if there is anti-aggregation effect on full-length TDP-43 tagged with YFP using the eukaryotic single cell yeast model by fluorescence microscopy
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