AQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models

Abstract

Edited by Joseph M. Jez Polyglutamine (polyQ) diseases are a group of dominantly inherited neurodegenerative disorders caused by the expansion of an unstable CAG repeat in the coding region of the affected genes. Hallmarks of polyQ diseases include the accumulation of misfolded protein aggregates, leading to neuronal degeneration and cell death. PolyQ diseases are currently incurable, highlighting the urgent need for approaches that inhibit the formation of disaggregate cytotoxic polyQ protein inclusions. Here, we screened for bisamidine-based inhibitors that can inhibit neuronal polyQ protein inclusions. We demonstrated that one inhibitor, AQAMAN, prevents polyQ protein aggregation and promotes de-aggregation of self-assembled polyQ proteins in several models of polyQ diseases. Using immunocytochemistry, we found that AQAMAN significantly reduces polyQ protein aggregation and specifically suppresses polyQ protein-induced cell death. Using a recombinant and purified polyQ protein (thioredoxin-Huntingtin-Q46), we further demonstrated that AQAMAN interferes with polyQ self-assembly, preventing polyQ aggregation, and dissociates preformed polyQ aggregates in a cell-free system. Remarkably, AQAMAN feeding of Drosophila expressing expanded polyQ disease protein suppresses polyQ-induced neurodegeneration in vivo. In addition, using inhibitors and activators of the autophagy pathway, we demonstrated that AQAMAN's cytoprotective effect against polyQ toxicity is autophagy-dependent. In summary, we have identified AQAMAN as a potential therapeutic for combating polyQ protein toxicity in polyQ diseases. Our findings further highlight the importance of the autophagy pathway in clearing harmful polyQ proteins.

Dynamics of a Protein Interaction Network Associated to the Aggregation of polyQ-Expanded Ataxin-1

“…At the moment, there is no available therapy for polyQ diseases, even though Rho/ROCK and MTOR inhibitors [ 55 , 56 ] or compounds entering the BBB [ 57 ] are suggested to suppress the aggregation of mutant proteins and may delay disease progression. Our approach indicates potential drug targets which are involved in the pathogenesis of HD and might be also relevant for SCA1.…”

Isolation and Identification of a Novel Anti-protein Aggregation Activity of Lignin-Carbohydrate Complex From Chionanthus retusus Leaves

“…In contrast to EGFP, which is prone to form dimers, AcGFP is a monomeric green fluorescent protein with equivalent brightness (Zacharias et al, 2002;Gurskaya et al, 2003). When AcGFP-ATXN3Q71 was expressed in our cell model, the number of ATXN3Q71 protein aggregates in each cell could be clearly detected and easily counted, while this is more difficult to achieve in EGFP-ATXNQ78-expressing cells (Hong et al, 2019).…”

“…As the pathological hallmark of polyQ diseases, the formation of polyQ protein aggregates in neurons impairs a range of normal biological functions and contributes to polyQ neurodegeneration ( Adegbuyiro et al, 2017 ). A series of chemical inhibitors, including small molecule compound ( Hong et al, 2019 ), synthetic peptide ( Nagai et al, 2003 ) and natural product extract ( Walter et al, 2014 ), have been reported to ameliorate polyQ cytotoxicity via lowering the level of polyQ protein aggregates. Moreover, several lines of evidence have demonstrated the neuroprotective roles of antioxidants in polyQ diseases ( Wu et al, 2017 ; Essa et al, 2019 ).…”

A fine balance between Prpf19 and Exoc7 in achieving degradation of aggregated protein and suppression of cell death in spinocerebellar ataxia type 3

“…When expressed in neuronal cell line SK-N-MC, mutant ATXN3-polyQ protein forms microscopic protein aggregates (ref. 45 ; Fig. 3a ).…”