Cordycepin activates autophagy through AMPK phosphorylation to reduce abnormalities in Machado–Joseph disease models

Abstract

Machado-Joseph disease (MJD) is a neurodegenerative disorder, caused by an abnormal expansion of CAG trinucleotide repeats in the disease-causing gene. This mutation leads to an abnormal polyglutamine tract in the protein ataxin-3, resulting in formation of mutant ataxin-3 aggregates. Despite several attempts to develop a therapeutic option for MJD, currently there are no available therapies capable of delaying or stopping disease progression. Recently, our group reported that reducing the expression levels of mutant ataxin-3 lead to a mitigation of several MJD-related behavior and neuropathological abnormalities. Aiming a more rapid translation to the human clinics, in this study we investigate a pharmacological inhibitor of translation - cordycepin - in several preclinical models. We found that cordycepin treatment significantly reduced: i) the levels of mutant ataxin-3; ii) the neuropathological abnormalities in a lentiviral mouse model; iii) the motor and neuropathological deficits in a transgenic mouse model and iv) the number of ubiquitin aggregates in a human neural model. We hypothesize that the effect cordycepin is mediated by the increase of phosphorylated AMPK levels, which is accompanied by a reduction in the global translation levels and by a significant activation of the autophagy pathway. Overall, this study suggests that cordycepin might constitute an effective and safe therapeutic approach for MJD, and probably for the other polyglutamine diseases.

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

“…Twenty-five mice were injected in the striatum with the lentiviral vectors and distributed into control (n = 13) and treatment groups (n = 12), which were orally administered with water and 2% trehalose solution, respectively. Accordingly to previously studies from our group [22,33], we expected to observe a positive effect of the treatment after 4 weeks administration, which would rationally be anticipated by an increase in autophagy. Thus, half of the animals (6 controls and 6 treated mice) were sacrificed after 2 weeks to evaluate autophagy markers and the other half (7 controls and 6 treated mice) after 4 weeks to evaluate neuropathology, by western blot and immunohistochemistry, respectively (Fig.…”

“…Histologically, this mouse model is characterized by the presence of ubiquitinated aggregates and the loss of Darpp-32 immunoreactivity [22,33]. Darpp-32 is a protein of the dopaminergic signaling pathway and loss of its immunoreactivity is indicative of early neuronal dysfunction.…”

Cordycepin ameliorates cardiac hypertrophy via activating the AMPKα pathway

“…28,29 AMPKα is an important sensor of cellular energy status, and that regulates this status in various pathophysiological processes. 30 One of the key characteristics of cardiac hypertrophy is increased protein synthesis and decreased protein degradation in cardiomyocytes, which leads to intracellular protein accumula- Although we have proven that cordycepin can ameliorate cardiac hypertrophy and have discussed the primary mechanism, our research has some limitations. First, we used CpC, an inhibitor of AMPKα, to conduct cell experiments in vitro, but we have not yet used this compound in animal experiments in vivo.…”

“…It has been reported that cordycepin can activate AMPKα (a serine/threonine protein kinase) signalling . AMPKα is an important sensor of cellular energy status, and that regulates this status in various pathophysiological processes . One of the key characteristics of cardiac hypertrophy is increased protein synthesis and decreased protein degradation in cardiomyocytes, which leads to intracellular protein accumulation.…”

New Synthetic 3-Benzoyl-5-Hydroxy-2H-Chromen-2-One (LM-031) Inhibits Polyglutamine Aggregation and Promotes Neurite Outgrowth through Enhancement of CREB, NRF2, and Reduction of AMPKα in SCA17 Cell Models

“…In accordance to these results, ours showed that LM-031 decreased aggregation, reduced ROS, and improved neurite outgrowth, which is mediated, at least partially, by reducing AMPKα phosphorylation. In contrast, cordycepin reduced aggregates and improved pathological abnormalities by enhancing autophagy, which is mediated through the activation of AMPK in two SCA3 mouse models [71]. Furthermore, activation of AMPK by A769662 and overexpression of an active form of AMPKα leads to improved cell viability in HD cell models [72].…”