Age-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD) are an unmet health need, with significant economic and societal implications, and an ever-increasing prevalence. Membrane lipid rafts (MLRs) are specialised plasma membrane microdomains that provide a platform for intracellular trafficking and signal transduction, particularly within neurons. Dysregulation of MLRs leads to disruption of neurotrophic signalling and excessive apoptosis which mirrors the final common pathway for neuronal death in ALS, PD and AD. Sphingomyelinase (SMase) and phospholipase (PL) enzymes process components of MLRs and therefore play central roles in MLR homeostasis and in neurotrophic signalling. We review the literature linking SMase and PL enzymes to ALS, AD and PD with particular attention to attractive therapeutic targets, where functional manipulation has been successful in preclinical studies. We propose that dysfunction of these enzymes is upstream in the pathogenesis of neurodegenerative diseases and to support this we provide new evidence that ALS risk genes are enriched with genes involved in ceramide metabolism (P=0.019, OR = 2.54, Fisher exact test). Ceramide is a product of SMase action upon sphingomyelin within MLRs, and it also has a role as a second messenger in intracellular signalling pathways important for neuronal survival. Genetic risk is necessarily upstream in a late age of onset disease such as ALS. We propose that manipulation of MLR structure and function should be a focus of future translational research seeking to ameliorate neurodegenerative disorders.
Aim: To investigate the biocompatibility of green synthesized copper oxide nanoparticles (CuO Np) using floral extract of Calotropis gigantea in room condition. Materials & methods: Green synthesized and characterized CuO Np was evaluated for their cellular and molecular biocompatibility by experimentally and computational molecular docking. Results: Synthesized CuO NP was found to have a size 32 ± 09 nm with ζ potential -35 ± 12 mV. LC50 value was found to be 190 μg/ml. In vitro and in silico cytotoxicity analysis with HEK293 cells revealed the cytotoxic effect of CuO Np as consequences of interaction with histidine and arginine amino acid residues of Sod3 and p53 proteins via hydrogen bond of length 3.09 and 3.32 Å leading to oxidative stress ensuing toward apoptosis and cell cycle arrest. Conclusion: The outcomes proved the synthesized material as an alternative to the conventional method of synthesizing copper nanoparticles for biomedical and clinical applications.
PGC-1α plays a central role in maintaining the mitochondrial and energy metabolism homeostasis, linking external stimuli to the transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and a putative RNA recognition motif, however potential RNA-processing role(s) have remained elusive for the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export factor NXF1. Inducible depletion of endogenous PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrate that the RNA-binding activity is required for nuclear export of co-activated transcripts and mitochondrial homeostasis. Moreover, a quantitative proteomics approach confirmed PGC-1α-dependent RNA transport and mitochondrial-related functions, identifying also novel mRNA nuclear export targets in age-related telomere maintenance. Discovering a novel function for a major cellular homeostasis regulator provides new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, ageing and neurodegenerative diseases.
Mutations within GLT8D1 contribute to familial amyotrophic lateral sclerosis. Pathogenic mutations impair GLT8D1 glycosyltransferase enzymatic function via a dominant negative mechanism, yet the downstream mechanism leading to neurotoxicity is unclear. Here we show that a p.R92C mutation causes fragmentation of the Golgi network and reduces ganglioside expression within membrane lipid rafts (MLRs), leading to impaired neurotrophin signalling. Expression of p.R92C-GLT8D1 in HEK293 cells and mouse primary neurons reduces expression of GM1 gangliosides within the cell plasma membrane leading to disruption of MLRs. Furthermore, p.R92C-GLT8D1 reduces TrkB-mediated pro-survival signalling in MLRs isolated from primary neurons. Interestingly, up-regulation of wild-type GLT8D1 enhances MLRs and promotes pro-survival signalling through TrkB. This closely mirrors findings for another ALS gene, CAV1, suggesting convergence on a common pathogenic pathway. Other ALS genes have been associated with Golgi dysfunction and may disrupt the same pathway, suggesting a potential new therapeutic approach via upregulation of GLT8D1.
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