Functional implications of NHR-210 enrichment in C. elegans cephalic sheath glia: insights into metabolic and mitochondrial disruptions in Parkinson's disease models.

Glial cells constitute nearly half of the mammalian nervous system's cellular composition. The glia in C. elegans perform majority of tasks comparable to those conducted by their mammalian equivalents. The cephalic sheath (CEPsh) glia, which are known to be the counterparts of mammalian astrocytes, are enriched with two nuclear hormone receptors (NHRs)-NHR-210 and NHR-231. This unique enrichment makes the CEPsh glia and these NHRs intriguing subjects of study concerning neuronal health. We endeavored to assess the role of these NHRs in neurodegenerative diseases and related functional processes, using transgenic C. elegans expressing human alpha-synuclein. We employed RNAi-mediated silencing, followed by behavioural, functional, and metabolic profiling in relation to suppression of NHR-210 and 231. Our findings revealed that depleting nhr-210 changes dopamine-associated behaviour and mitochondrial function in human alpha synuclein-expressing strains NL5901 and UA44, through a putative target, pgp-9, a transmembrane transporter. Considering the alteration in mitochondrial function and the involvement of a transmembrane transporter, we performed metabolomics study via HR-MAS NMR spectroscopy. Remarkably, substantial modifications in ATP, betaine, lactate, and glycine levels were seen upon the absence of nhr-210. We also detected considerable changes in metabolic pathways such as phenylalanine, tyrosine, and tryptophan biosynthesis metabolism; glycine, serine, and threonine metabolism; as well as glyoxalate and dicarboxylate metabolism. In conclusion, the deficiency of the nuclear hormone receptor nhr-210 in alpha-synuclein expressing strain of C. elegans, results in altered mitochondrial function, coupled with alterations in vital metabolite levels. These findings underline the functional and physiological importance of nhr-210 enrichment in CEPsh glia.

Multiple checkpoints of protein clearance machinery are modulated by a common microRNA, miR-4813-3p, through its putative target genes: Studies employing transgenic C. elegans model.

In order to maintain cellular homeostasis and a healthy state, aberrant and aggregated proteins are to be recognized and rapidly cleared from cells. Parkinson's disease, known to be associated with multiple factors; presents with impaired clearance of aggregated alpha synuclein as a key factor. We endeavored to study microRNA molecules with potential role on regulating multiple checkpoints of protein quality control within cells. Carrying out global miRNA profiling in a transgenic C. elegans model that expresses human alpha synuclein, we identified novel miRNA, miR-4813-3p, as a significantly downregulated molecule. Further studying its putative downstream target genes, we were able to mechanistically characterize six genes gbf-1, vha-5, cup-5, cpd-2, acs-1 and C27A12.7, which relate to endpoints associated with alpha synuclein expression, oxidative stress, locomotory behavior, autophagy and apoptotic pathways. Our study reveals the novel role of miR-4813-3p and provides potential functional characterization of its putative target genes, in regulating the various pathways associated with PQC network. miR-4813-3p modulates ERUPR, MTUPR, autophagosome-lysosomal-pathway and the ubiquitin-proteasomal-system, making this molecule an interesting target for further studies towards therapeutically addressing multifactorial aspect of Parkinson's disease.

Food-Grade Quercetin-Loaded Nanoemulsion Ameliorates Effects Associated with Parkinson's Disease and Cancer: Studies Employing a Transgenic C. elegans Model and Human Cancer Cell Lines.

A nanosized food-grade quercetin-loaded nanoemulsion (QNE) system comprising capmul MCM NF (oil) and cremophor RH 40 (surfactant) was developed using a high-speed homogenization technique. The developed QNE was studied for its significant neuroprotective (anti-Parkinsonism) and cytotoxicity (anticancer) effects against Caenorhabditis elegans (C. elegans) strains and human cancer cells, respectively. HR-TEM studies revealed that the QNE was spherical with a mean globule size of ~50 nm. Selected area electron diffraction (SAED) studies results demonstrated that QNE was amorphous. In vivo results show that QNE potentially reduced the α-Syn aggregation, increased mitochondrial and fat content, and improved the lifespan in transgenic C. elegans strain NL5901. QNE significantly downregulated the reactive oxygen species (ROS) levels in wild-type C. elegans strain N2. In vitro results of the MTT assay show that QNE significantly exhibited chemotherapeutic effects in all treated human cancer cells in an order of cytotoxicity: HeLa cells > A549 cells > MIA PaCa-2 cells, based on the IC50 values at 24 h. Conclusively, the QNE showed improved solubility, targetability, and neuroprotective effects against the PD-induced C. elegans model, and also cytotoxicity against human cancer cells and could be potentially used as an anti-Parkinson's or anticancer agent.

Carrying Excess Baggage Can Slowdown Life: Protein Clearance Machineries That Go Awry During Aging and the Relevance of Maintaining Them.

Cellular homeostasis is maintained by rapid and systematic cleansing of aberrant and aggregated proteins within cells. Neurodegenerative diseases (NDs) especially Parkinson's and Alzheimer's disease are known to be associated with multiple factors, most important being impaired clearance of aggregates, resulting in the accumulation of specific aggregated protein in the brain. Protein quality control (PQC) of proteostasis network comprises proteolytic machineries and chaperones along with their regulators to ensure precise operation and maintenance of proteostasis. Such regulatory factors coordinate among each other multiple functional aspects related to proteins, including their synthesis, folding, transport, and degradation. During aging due to inevitable endogenous and external stresses, sustaining a proteome balance is a challenging task. Such stresses decline the capacity of the proteostasis network compromising the proteome integrity, affecting the fundamental physiological processes including reproductive fitness of the organism. This review focuses on highlighting proteome-wide changes during aging and the strategies for proteostasis improvements. The possibility of augmenting the proteostasis network either via genetic or pharmacological interventions may be a promising strategy towards delaying age-associated pathological consequences due to proteome disbalance, thus promoting healthy aging and prolonged longevity.

Genetic modulators associated with regulatory surveillance of mitochondrial quality control, play a key role in regulating stress pathways and longevity in C. elegans.

The multi-factorial Parkinson's disease (PD) is known to be associated with mitochondrial dysfunction, endoplasmic reticulum stress, alpha synuclein aggregation and dopaminergic neuronal death, with oxidative stress being a common denominator to these underlying processes. The perception of mitochondria being 'just ATP producing compartments' have been counterpoised as studies, particularly related to PD, have underlined their strong role in cause and progression of the disease. During PD pathogenesis, neurons encounter chronic stress conditions mainly due to failure of Mitochondrial Quality Control (MQC) machinery. To dissect the regulatory understanding of mitochondrial dysfunction during neurological disease progression, we endeavored to identify key regulatory endpoints that control multiple facets of MQC machinery. Our studies, employing transgenic C. elegans strain expressing human α-synuclein, led us to identification of mitochondrial genes nuo-5 (involved in oxidative phosphorylation), F25B4.7 (exhibits ATP transmembrane transporter activity) and C05D11.9 (having ribonuclease activity), which form predicted downstream targets of most elevated and down-regulated mi-RNA molecules. RNAi mediated silencing, gene ontology and functional genomics analysis studies demonstrated their role in modulating major MQC pathways. The attenuated MQC pathways mainly affected clearance of misfolded and aggregated proteins, redox homeostasis and longevity with compromised dopaminergic functions. Overexpression of the mitochondrial genes by 3 beta-hydroxyl steroid, Tomatidine, was found to curtail the redox imbalance thus leading to amelioration of effects associated with PD and an increase in the lifespan of treated nematodes. Therefore, this study unveils the regulatory role of mitochondrial genes as critical modulators of stress control involved in effects associated with PD pathogenesis.

The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model.

The conserved B-subunit of succinate dehydrogenase (SDH) participates in the tricarboxylic acid cycle (TCA) cycle and mitochondrial electron transport. The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL). In Caenorhabditiselegans, we generated an in vivo PPGL model (SDHB-1 Arg244His; equivalent to human Arg230His), which manifests delayed development, shortened lifespan, attenuated ATP production and reduced mitochondrial number. Although succinate is elevated in both missense and null sdhb-1(gk165) mutants, transcriptomic comparison suggests very different causal mechanisms that are supported by metabolic analysis, whereby only Arg244His (not null) worms demonstrate elevated lactate/pyruvate levels, pointing to a missense-induced, Warburg-like aberrant glycolysis. In silico predictions of the SDHA-B dimer structure demonstrate that Arg230His modifies the catalytic cleft despite the latter's remoteness from the mutation site. We hypothesize that the Arg230His SDHB mutation rewires metabolism, reminiscent of metabolic reprogramming in cancer. Our tractable model provides a novel tool to investigate the metastatic propensity of this familial cancer and our approach could illuminate wider SDH pathology.This article has an associated First Person interview with the first author of the paper.