It is well-recognized that the gut microbiota (GM) is crucial for gut function, metabolism, and energy cycles. The GM also has effects on neurological outcomes via many mechanisms, such as metabolite production and the gut-brain axis. Emerging evidence has gradually indicated that GM dysbiosis plays a role in several neurological diseases, such as Parkinson's disease (PD), Alzheimer's disease, depression, and multiple sclerosis. Several studies have observed that PD patients generally suffer from gastrointestinal disorders and GM dysbiosis prior to displaying motor symptoms, but the specific link between the GM and PD is not clearly understood. In this review, we aim to summarize what is known regarding the correlation between the GM and PD pathologies, including direct, and indirect evidence.
Prion diseases caused by the cellular prion protein (PrPC) conversion into a misfolded isoform (PrPSc) are associated with multiple mitochondrial damages. We previously reported mitochondrial dynamic abnormalities and cell death in prion diseases via modulation of a variety of factors. Optic atrophy 1 (OPA1) is one of the factors that control mitochondrial fusion, mitochondrial DNA (mtDNA) maintenance, bioenergetics, and cristae integrity. In this study, we observed downregulation of OPA1 in prion disease models in vitro and in vivo, mitochondria structure damage and dysfunction, loss of mtDNA, and neuronal apoptosis. Similar mitochondria findings were seen in OPA1-silenced un-infected primary neurons. Overexpression of OPA1 not only alleviated prion-induced mitochondrial network fragmentation and mtDNA loss, decrease in intracellular ATP, increase in ADP/ATP ratio, and decrease in mitochondrial membrane potential but also protected neurons from apoptosis by suppressing the release of cytochrome c from mitochondria to cytosol and activation of the apoptotic factor, caspase 3. Our results demonstrated that overexpression of OPA1 alleviates prion-associated mitochondrial network fragmentation and cristae remodeling, mitochondrial dysfunction, mtDNA depletion, and neuronal apoptosis, suggesting that OPA1 may be a novel and effective therapeutic target for prion diseases.
A persistent accumulation of damaged mitochondria is part of prion disease pathogenesis. Normally, damaged mitochondria are cleared via a major pathway that involves the E3 ubiquitin ligase parkin and PTEN-induced kinase 1 (PINK1) that together initiate mitophagy, recognize and eliminate damaged mitochondria. However, the precise mechanisms underlying mitophagy in prion disease remain largely unknown. Using prion disease cell models, we observed PINK1-parkin-mediated mitophagy deficiency in which parkin depletion aggravated blocked mitochondrial colocalization with LC3-II-labeled autophagosomes, and significantly increased mitochondrial protein levels, which led to inhibited mitophagy. Parkin overexpression directly induced LC3-II colocalization with mitochondria and alleviated defective mitophagy. Moreover, parkin-mediated mitophagy was dependent on PINK1, since PINK1 depletion blocked mitochondrial Parkin recruitment and reduced optineurin and LC3-II proteins levels, thus inhibiting mitophagy. PINK1 overexpression induced parkin recruitment to the mitochondria, which then stimulated mitophagy. In addition, overexpressed parkin and PINK1 also protected neurons from apoptosis. Furthermore, we found that supplementation with two mitophagy-inducing agents, nicotinamide mononucleotide (NMN) and urolithin A (UA), significantly stimulated PINK1-parkin-mediated mitophagy. However, compared with NMN, UA could not alleviate prion-induced mitochondrial fragmentation and dysfunction, and neuronal apoptosis. These findings show that PINK1-parkin-mediated mitophagy defects lead to an accumulation of damaged mitochondria, thus suggesting that interventions that stimulate mitophagy may be potential therapeutic targets for prion diseases.
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