Background: N6-methyladenosine (m⁶A) modification of RNA influences fundamental aspects of RNA metabolism and m⁶A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m⁶A modification in the pathogenesis of Alzheimer disease (AD).Methods: We investigated the m⁶A modification and the expression of m⁶A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m⁶A levels on AD-related deficits both in vitro and in vivo.Results: We found decreased neuronal m⁶A levels along with significantly reduced expression of m⁶A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m⁶A modification in the hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied by extensive synaptic loss and neuronal death along with multiple AD-related cellular alterations including oxidative stress and aberrant cell cycle events in vivo. Inhibition of oxidative stress or cell cycle alleviated shMettl3-induced apoptotic activation and neuronal damage in primary neurons. Restored m⁶A modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble Aβ oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued Aβ-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued Aβ-induced synaptic damage and cognitive impairment in vivo.Conclusions: Collectively, these data suggested that METTL3 reduction-mediated m⁶A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.

Mitochondrial dysfunction represents a critical event in the pathogenesis of Parkinson’s disease (PD). Increasing evidence demonstrates that disturbed mitochondrial dynamics and quality control play an important role in mitochondrial dysfunction in PD. Our previous study demonstrated that MPP⁺ induces mitochondrial fragmentation in vitro. In this study, we aimed to assess whether blocking MPTP-induced mitochondrial fragmentation by overexpressing Mfn2 affords neuroprotection in vivo. We found that the significant loss of dopaminergic neurons in the substantia nigra (SN) induced by MPTP treatment, as seen in wild-type littermate control mice, was almost completely blocked in mice overexpressing Mfn2 (hMfn2 mice). The dramatic reduction in dopamine neuronal fibers and dopamine levels in the striatum caused by MPTP administration was also partially inhibited in hMfn2 mice. MPTP-induced oxidative stress and inflammatory response in the SN and striatum were significantly alleviated in hMfn2 mice. The impairment of motor function caused by MPTP was also blocked in hMfn2 mice. Overall, our work demonstrates that restoration of mitochondrial dynamics by Mfn2 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which supports the modulation of mitochondrial dynamics as a potential therapeutic target for PD treatment.

Parkinson’s disease (PD) is a neurodegenerative disorder classified by the loss of dopaminergic neurons in the substantia nigra pars compacta, the region of the brain that is responsible for motor control. Surviving neurons in this region contain aggregated protein alpha-Synuclein (αSyn) in the form of cytoplasmic inclusions, referred to as Lewy bodies. Changes in αSyn expression are also associated with PD and its progression. Previously, we demonstrated that signal recognition particle (SRP) and Argonaute 2 (AGO2) proteins are involved in protein quality control at the ribosome during translation. We also demonstrated that SRP has an mRNA protection function in addition to a protein targeting function, thus controlling mRNA and protein expression. In this study, we tested involvement of these factors in αSyn biogenesis. We hypothesize that loss of these factors may interfere with αSyn expression, and subsequently, be associated with PD. Using depletion assays in human cell culture and analysis of these proteins in the brains of deceased PD patients, we demonstrate that SRP and AGO2 are involved in the control of αSyn expression and AGO2 has reduced expression in PD. We show for the first time that SRP is involved in mRNA protection of αSyn, a protein that does not have a signal sequence or transmembrane span. Our findings suggest that SRP may interact with a hydrophobic domain in the middle of αSyn during translation. Understanding the molecular mechanisms controlling αSyn biogenesis in cells is vital to developing preventative therapies against PD.

Background: Mitochondrial dysfunction is a major pathological event of neurodegeneration including Alzheimer’s disease (AD). Expanding evidence demonstrate that an altered balance in mitochondrial dynamics is an important mechanism leading to mitochondrial and neuronal dysfunction during neurodegeneration. Thus, it is of great interest to test if restoration of mitochondrial dynamics has beneficial role in AD treatment. Method: 5xFAD mouse model of AD was used to test whether MFN2 OE or MFN2 activator rescues mitochondrial dysfunctions and neurodegeneration. Behavioral tests, mitochondrial analysis, electrophysiological study, RNA‐seq and biochemical analysis were applied to examine the brain pathology in the AD mouse model. Result: In this study, we observed fragmented and damaged mitochondria in 5xFAD mouse brains, along with impaired mitochondrial respiration of synaptosome at 6 months. Restoration of mitochondrial dynamics by conditional overexpression (OE) of mitofusin‐2 (MFN2) in forebrain neurons rescues mitochondrial fragmentation and dysfunction in 5xFAD mouse brains. Importantly, MFN2 OE protects against long‐term potential reduction, synaptic loss, oxidative stress damage, amyloid plaque size, neuroinflammation and cognitive deficits in 5xFAD mice at 6 months. Amyloid plaque burden and neuronal death in plaque‐enriched layer V cortical regions can be alleviated in 5xFAD mice by MFN2 OE at 10 months. RNA sequencing (RNA‐seq) reveals disturbed transcriptomic profiles including increased inflammatory responses in 5xFAD mice, which is reversed by MFN2 OE. Specifically, MFN2 OE inhibits microglial activation, proinflammatory cytokine production, and NLRP3 inflammasome activation in 5xFAD mice. Lastly, intraperitoneal injection of compound BAY2402234, a brain penetrant MFN2 activator, rescues mitochondrial fragmentation, oxidative damage, and memory deficits in 5xFAD mice. Conclusion: Overall, our study demonstrated that the restoration of mitochondrial dynamics by inhibition of mitochondrial fragmentation can protect against neurodegeneration in 5xFAD mouse model and mitochondrial dynamic could be a promising therapeutic target for AD.

Enterovirus A71 infection can cause hand, foot, and mouth disease to occasionally develop the severe neurological complications, but how peripheral Enterovirus A71 infection affects the blood-brain barrier remains incompletely understood. Here, we show that Enterovirus A71 infection of peripheral susceptible cells increases the release of extracellular vesicles and promotes the enrichment of microRNA-30 and microRNA-34 within these vesicles. The extracellular vesicle-associated microRNAs suppress Notch1 signaling in human brain microvascular endothelial cells, impair endothelial junctional integrity, and increase blood-brain barrier permeability. Activation of Notch1 signaling restores barrier integrity and reduces viral neuroinvasion in neonatal mice. Clinically, serum extracellular vesicle-associated microRNA-30 and microRNA-34 are elevated in patients with severe Enterovirus A71-associated hand, foot, and mouth disease. Together, our findings identify circulating extracellular vesicles as mediators linking peripheral Enterovirus A71 infection to blood-brain barrier dysfunction and suggest that the microRNA-30/34–Notch1 axis contributes to neurological disease progression during severe Enterovirus A71 infection.