FTO-targeted siRNA delivery by MSC-derived exosomes synergistically alleviates dopaminergic neuronal death in Parkinson's disease via m6A-dependent regulation of ATM mRNA

Abstract

Background Parkinson's disease (PD), characterized by the progressive loss of dopaminergic neurons in the substantia nigra and striatum of brain, seriously threatens human health, and is still lack of effective treatment. Dysregulation of N6-methyladenosine (m6A) modification has been implicated in PD pathogenesis. However, how m6A modification regulates dopaminergic neuronal death in PD remains elusive. Mesenchymal stem cell-derived exosomes (MSC-Exo) have been shown to be effective for treating central nervous disorders. We thus propose that the m6A demethylase FTO-targeted siRNAs (si-FTO) may be encapsulated in MSC-Exo (Exo-siFTO) as a synergistic therapy against dopaminergic neuronal death in PD. Methods In this study, the effect of m6A demethylase FTO on dopaminergic neuronal death was evaluated both in vivo and in vitro using a MPTP-treated mice model and a MPP + -induced MN9D cellular model, respectively. The mechanism through which FTO influences dopaminergic neuronal death in PD was investigated with qRT-PCR, western blot, immumohistochemical staining, immunofluorescent staining and flow cytometry. The therapeutic roles of MSC-Exo containing si-FTO were examined in PD models in vivo and in vitro. Results The total m6A level was significantly decreased and FTO expression was increased in PD models in vivo and in vitro. FTO was found to promote the expression of cellular death-related factor ataxia telangiectasia mutated (ATM) via m6A-dependent stabilization of ATM mRNA in dopaminergic neurons. Knockdown of FTO by si-FTO concomitantly suppressed upregulation of α-Synuclein (α-Syn) and downregulation of tyrosine hydroxylase (TH), and alleviated neuronal death in PD models. Moreover, MSC-Exo were utilized to successfully deliver si-FTO to the striatum of animal brain, resulting in the significant suppression of α-Syn expression and dopaminergic neuronal death, and recovery of TH expression in the brain of PD mice. Conclusions MSC-Exo delivery of si-FTO synergistically alleviates dopaminergic neuronal death in PD via m6A-dependent regulation of ATM mRNA.

Mapping the Research of Ferroptosis in Parkinson’s Disease from 2013 to 2023: A Scientometric Review

“… 136 , 137 Angelova et al discovered that α-syn oligomers can bind to cell membranes and induce ferroptosis by driving lipid peroxidation. 40 Furthermore, research findings indicate that α-syn plays a role in metabolizing essential membrane PUFAs like arachidonic acid (AA), 6 , 138 including increasing its membrane fluidity and regulating vesicle assembly and synaptic transmission. 109 , 138 , 139 A recent study utilizing transmission electron microscopy (TEM) and optical microscopy imaging technologies suggested that the immunoreactivity of α-syn in LB is closely linked to high levels of membrane lipids, fragmented organelles, and vesicles.…”

“…The gradual degeneration of dopaminergic neurons in the substantia nigra (SN), along with abnormally aggregated α-synuclein (α-syn) forming Lewy bodies, are the pathological hallmarks of PD. 6 Although the current dopamine-based pharmacological therapies can alleviate motor symptoms in early-stage patients, there is a lack of effective neuroprotective treatment methods to prevent PD from progressively deteriorating. Therefore, investigating the underlying mechanisms of PD to explore novel targets and develop the next generation of therapies is urgently needed.…”

Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles

“…Further, miRNA-enriched EVs have been shown to exert neuroprotective effects, with miR-29 and miR-22 variants downregulating pathological Aβ production and inflammatory cascades in AD models [156,157]. Additionally, m6A modifications in RNA processes, implicated in PD, have been targeted using MSC-EVs to deliver demethylase FTO-targeted siRNAs, demonstrating neuroprotective outcomes [158].…”

Potential role of N6-methyladenosine modification in the development of Parkinson’s disease

“…They suggested that FTO affects ATM expression by influencing the stability of ATM mRNA in dopaminergic neurons. FTO knockdown inhibited ATM expression, suppressing the upregulation of α-Syn and the downregulation of tyrosine hydroxylase (TH), thereby alleviating dopaminergic neuron death in vitro in a PD model ( Geng et al, 2023 ).…”