Necrosulfonamide exerts neuroprotective effect by inhibiting necroptosis, neuroinflammation, and α-synuclein oligomerization in a subacute MPTP mouse model of Parkinson’s disease

While the etiology of most cases of Parkinson's disease (PD) are idiopathic, is has been estimated that 5-10 percent of PD arise from known genetic mutations. The first mutations described that leads to the development of an autosomal dominant form of PD are in the SNCA gene that codes for the protein alpha-synuclein (alpha-syn). alpha-syn is an abundant presynaptic protein that is natively disordered and whose function is still unclear. In PD, alpha-syn misfolds into multimeric beta-pleated sheets that aggregate in neurons (Lewy Bodies/neurites) and spread throughout the neuraxis in a pattern that aligns with disease progression. Here, using IHC, HPLC, and cytokine analysis, we examined the sequelae of intraparenchymal brain seeding of oligomeric pre-formed fibrils (PFFs) and monomeric a-syn in C57BL/6J (WT) and A53T SNCA mutant mice. We found that injection of PFFs, but not monomeric alpha-syn, into the striatum of C57BL/6J mice induced spread of aggregate alpha-syn, loss of SNpc DA neurons and increased neuroinflammation. However, in A53T SNCA mice, we found that both PFFs and monomeric alpha-syn induced this pathology. This suggests that the conformation changes in alpha-syn seen in the A53T strain can recruit wild-type alpha-syn to a pathological misfolded conformation which may provide a mechanism for the induction of PD in humans with SNCA duplication/triplication.

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GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy

Fu,

Zhang,

Shi

et al. 2024

J Neuroinflammation

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Background Gasdermin D (GSDMD)-mediated pyroptotic cell death is implicated in the pathogenesis of cognitive deficits in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain largely unclear. Dynamin-related protein 1 (Drp1) facilitates mitochondrial fission and ensures quality control to maintain cellular homeostasis during infection. This study aimed to investigate the potential role of the GSDMD/Drp1 signaling pathway in cognitive impairments in a mouse model of SAE. Methods C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to establish an animal model of SAE. In the interventional study, mice were treated with the GSDMD inhibitor necrosulfonamide (NSA) or the Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1). Surviving mice underwent behavioral tests, and hippocampal tissues were harvested for histological analysis and biochemical assays at corresponding time points. Haematoxylin-eosin staining and TUNEL assays were used to evaluate neuronal damage. Golgi staining was used to detect synaptic dendritic spine density. Additionally, transmission electron microscopy was performed to assess mitochondrial and synaptic morphology in the hippocampus. Local field potential recordings were conducted to detect network oscillations in the hippocampus. Results CLP induced the activation of GSDMD, an upregulation of Drp1, leading to associated mitochondrial impairment, neuroinflammation, as well as neuronal and synaptic damage. Consequently, these effects resulted in a reduction in neural oscillations in the hippocampus and significant learning and memory deficits in the mice. Notably, treatment with NSA or Mdivi-1 effectively prevented these GSDMD-mediated abnormalities. Conclusions Our data indicate that the GSDMD/Drp1 signaling pathway is involved in cognitive deficits in a mouse model of SAE. Inhibiting GSDMD or Drp1 emerges as a potential therapeutic strategy to alleviate the observed synaptic damages and network oscillations abnormalities in the hippocampus of SAE mice.

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Necrosulfonamide exerts neuroprotective effect by inhibiting necroptosis, neuroinflammation, and α-synuclein oligomerization in a subacute MPTP mouse model of Parkinson’s disease

Cited by 4 publications

References 58 publications

Creatine supplementation with exercise reduces α-synuclein oligomerization and necroptosis in Parkinson's disease mouse model

Creatine supplementation with exercise reduces α-synuclein oligomerization and necroptosis in Parkinson's disease mouse model

Templating of Monomeric Alpha-Synuclein Induces Inflammation and SNpc Dopamine Neuron Death in a Genetic Mouse Model of Synucleinopathy

GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy

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