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Two Human Metabolites Rescue a C. Elegans Model of Alzheimer’S

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Two Human Metabolites Rescue a C. Elegans Model of Alzheimer’S ARTICLE https://doi.org/10.1038/s42003-021-02218-7 OPEN Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response ✉ Priyanka Joshi 1,3 , Michele Perni 1, Ryan Limbocker1,4, Benedetta Mannini 1, Sam Casford1, Sean Chia1, ✉ Johnny Habchi1, Johnathan Labbadia2, Christopher M. Dobson 1 & Michele Vendruscolo 1 Age-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been exten- 1234567890():,; sively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Data- base, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzhei- mer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J- proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegen- erative disorders. 1 Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, UK. 2 Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London, UK. 3Present address: The California Institute for Quantitative Biosciences (QB3-Berkeley), University of California, Berkeley, CA, USA. 4Present address: Department of Chemistry and Life Science, United States Military Academy, ✉ West Point, NY, USA. email: [email protected]; [email protected] COMMUNICATIONS BIOLOGY | (2021) 4:843 | https://doi.org/10.1038/s42003-021-02218-7 | www.nature.com/commsbio 1 ARTICLE COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02218-7 lzheimer’s disease (AD) is a complex disorder character- inflammation, mitochondrial function, oxidative stress, neuronal ized by the presence of aberrant protein deposits in brain network excitability, metal ion homeostasis, autophagy, hypo- A 1–3 tissues . Although the molecular origins of this disease thalamic regulation, adult neurogenesis, and protein homeostasis are still to be firmly established, it is generally recognized that the (Fig. 1)1,15–28. Small molecule metabolites play key roles in these presence of protein deposits is associated with the dysregulation biochemical processes, but it is still not known in detail which of the protein homeostasis network4,5. In turn, this system is part among these roles are first dysregulated and are associated with of a wider cellular homeostasis system, which includes a variety of the pathophysiological onset and progression of the disease. other components, including the metabolite homeostasis In this context, whether the phenomenon of protein misfolding system6,7. and aggregation is a cause or a consequence of the impairment in Metabolites affect key steps in cellular pathways where they act these biological processes is yet to be firmly established. A wide as substrates for enzymes or as signaling molecules for the acti- range of studies has indicated that protein aggregation can vation of biochemical pathways. For example, caloric restriction directly result in activation of the downstream biochemical cas- and intermittent fasting retard structural and functional decline cades that significantly advance the pathology of AD29. The toxic during aging in laboratory rodents and monkeys8–10. Moreover, aggregate species are recognized to be Aβ and Tau oligomers, signaling pathways have evolved to respond to cellular stresses in whose abnormal interaction with cellular components can impair aging, with the AMPK and mTOR pathways being widely studied neuronal functions29,30. Given our present understanding of AD, in cellular development and ageing11–14. It is therefore important slowing or inhibiting protein aggregation may contribute to to understand how neurodegenerative disorders associated with preventing the advancement of the disease. Thus, understanding aging, such as AD, are linked with aberrations in cellular which pathways contribute towards this objective can offer homeostasis. The specific hypothesis that we investigate here is insightful windows of opportunity for preventative and ther- whether the dysregulation of metabolite levels is associated with apeutic interventions, as well as provide guidelines for sustainable the aberrant aggregation of proteins in AD. We approach this by ways of living (e.g. lifestyle factors, exercise, and diet) that sup- testing if supplementing the dysregulated metabolites may pre- press AD and promote healthy aging. vent or clear aggregation of misfolded proteins. In healthy organisms, protein aggregation is prevented by The impairment of various biological processes contributes to specific branches of the protein homeostasis system, in particular the onset and progression of AD, including DNA repair, the cytosolic heat shock response (HSR), for cytoplasmic folding Neuronal Network Excitability a (Voltage gated sodium, ATP, Oxidative Stress Metal Ion Homeostasis Potassium channels, glucose, (Ca2+ homeostasis) ketogenic diet) (Reactive Oxygen species (ROS)) Impaired Autophagy Mitochondrial Dysfunction (Acetyl CoA, polyamines, amino acids, insulin, leptin) (ATP, NAD+, NADH, Citrate) Neurofibrillary tangles Hallmarks of (Tau) Alzheimer’s Hypothalamus Disease Inflammation A plaques (hormones - vasopressin, Disrupted (lipids, vitamins, neurotransmitters, somatostatin) Energy Homeostasis hormones) DNA Repair Adult Neurogenesis (lipids, hormones - leptin, (insulin signaling, NAD+ dependent ghrelin, DHA, lactate) enzymes, purines, pyrimidines) Dysregulated Protein Homeostasis (Abnormal Protein Aggregation) Rebalancing protein homeostasis by restoring b Imbalance in Alzheimer’s disease metabolite homeostasis Metabolites as A , Tau A ,Tau aggregation small molecule aggregation proteostasis Aging regulators Aging Chaperones Probe Chaperones Clearance Protein Damage Protein Damage molecular Mechanisms Clearance mechanisms of Energetic Deficits Detoxifying Energetic Deficits Mechanisms action of Enzymes Detoxifying metabolites in Mutation Mutation Biosynthetic errors Enzymes Biosynthetic errors maintaining Protein Homeostasis protein Protein Homeostasis homeostasis Fig. 1 Metabolite homeostasis and protein homeostasis in Alzheimer’s disease (AD). a AD is associated with a wide range of dysfunctions in cellular homeostasis (colored boxes). A variety of endogenous metabolites are involved in regulating these cellular processes (gray box insets). b Small molecule endogenous metabolites can modulate the protein aggregation processes associated with the disease. By designing systematic studies we can uncover the exact molecular mechanisms by which they balance protein homeostasis. 2 COMMUNICATIONS BIOLOGY | (2021) 4:843 | https://doi.org/10.1038/s42003-021-02218-7 | www.nature.com/commsbio COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02218-7 ARTICLE and misfolding, and the unfolded protein responses (UPR) in the dysregulated in neurodegeneration (Supplementary Data 1). In endoplasmic reticulum and mitochondria31,32. Many heat shock the case of dysregulation, the levels of upregulation and proteins from the HSR are molecular chaperones that guide the downregulation of these metabolites are available from the conformation of proteins during biogenesis and prevent the HMDB and associated literature available therein. We then misfolding and aggregation that interfere with cellular function21. performed a literature search to corroborate the dysregulated Since the cytoplasm is also a pool of various metabolites produced status of the metabolites in neurodegeneration. We ranked this and shuttled across biochemical networks, it is expected that their status as an association score, by performing a PubMed search levels and threshold concentrations in the cell may have an effect (see the “Methods” section) (Supplementary Data 1). In principle, as small molecule regulators on the protein homeostasis network, the association score describes the association of AD with the thus keeping aggregation-prone proteins in their soluble state. identified endogenous metabolite across studies reported in Patel and colleagues showed that ATP enhances protein solu- PubMed. Classifying the identified metabolites into upregulated bility at physiological concentrations (mM range)33. One can thus and downregulated gives an insight into the effects of their envisage that other endogenous metabolites may also contribute normal concentrations on maintaining cellular homeostasis and to the modulation of protein aggregation. their dysregulation in disease. Enhanced expression of molecular chaperones, which is pri- We found 186 of the 380 endogenous CSF metabolites to be marily regulated by the transcription factor heat shock factor 1 dysregulated in neurodegeneration (Supplementary Data 1). We (HSF-1), has been shown to restore protein homeostasis in a then focused on six of these metabolites: 1-methylhistidine, variety of protein misfolding disease
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