Neurotransmitter loaded DNA nanocages as potential therapeutics for α-synuclein based neuropathies in cells and in vivo

Abstract

Parkinsons disease is one of the neuropathies characterized by accumulation of -synuclein protein, leading to motor dysfunction. Levodopa is the gold standard treatment, however, in long term usage, it leads to levodopa induced dyskinesia (LID). New therapeutic options are need of the hour to treat the -synuclein based neuropathies. The role of imbalance of neurotransmitters other than dopamine has been underestimated in -synuclein based neuropathies. Here, we explore the role of serotonin, epinephrine and norepinephrine as a therapeutic moiety. For the efficient in vivo delivery, we use DNA nanotechnology-based DNA tetrahedra that has shown the potential to cross the biological barriers. In this study, we explore the use of DNA nanodevices, particularly DNA tetrahedron functionalized with neurotransmitters, as a novel therapeutic approach for MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinsons disease in PC12 cellular system. We first establish the effect of these nanodevices on clearance of -synuclein protein in cells. We follow the study by understanding the various cellular processes like ROS, iron accumulation and lipid peroxidation. We also explore the effect of the neurotransmitter loaded nanodevices in in vivo zebrafish model. We show that neurotransmitter loaded DNA nanocages can potentially clear the MPTP induced -synuclein aggregates in cells and in vivo. The findings of these work open up new avenues for use of DNA nanotechnology by functionalizing it with neurotransmitters for future therapeutics in treatment of neurodegenerative diseases such as Parkinsons disease. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/626934v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@94c347org.highwire.dtl.DTLVardef@a08756org.highwire.dtl.DTLVardef@1153704org.highwire.dtl.DTLVardef@1cefebb_HPS_FORMAT_FIGEXP M_FIG C_FIG TD:NT can clear -synuclein by targeting the ferroptosis pathway.