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1.
PLoS Genet ; 19(9): e1010893, 2023 09.
Article in English | MEDLINE | ID: mdl-37733679

ABSTRACT

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.


Subject(s)
Alzheimer Disease , Frontotemporal Dementia , Humans , Animals , Frontotemporal Dementia/genetics , Alzheimer Disease/genetics , Neuroglia , Pyruvic Acid , Drosophila , Glucose
2.
Cell Metab ; 31(4): 710-725.e7, 2020 04 07.
Article in English | MEDLINE | ID: mdl-32197072

ABSTRACT

High-sugar diets cause thirst, obesity, and metabolic dysregulation, leading to diseases including type 2 diabetes and shortened lifespan. However, the impact of obesity and water imbalance on health and survival is complex and difficult to disentangle. Here, we show that high sugar induces dehydration in adult Drosophila, and water supplementation fully rescues their lifespan. Conversely, the metabolic defects are water-independent, showing uncoupling between sugar-induced obesity and insulin resistance with reduced survival in vivo. High-sugar diets promote accumulation of uric acid, an end-product of purine catabolism, and the formation of renal stones, a process aggravated by dehydration and physiological acidification. Importantly, regulating uric acid production impacts on lifespan in a water-dependent manner. Furthermore, metabolomics analysis in a human cohort reveals that dietary sugar intake strongly predicts circulating purine levels. Our model explains the pathophysiology of high-sugar diets independently of obesity and insulin resistance and highlights purine metabolism as a pro-longevity target.


Subject(s)
Dehydration/chemically induced , Obesity/chemically induced , Sugars/adverse effects , Water/metabolism , Animals , Drosophila/physiology , Humans , Insulin Resistance , Longevity
3.
Curr Biol ; 28(11): 1714-1724.e4, 2018 06 04.
Article in English | MEDLINE | ID: mdl-29779873

ABSTRACT

Intermittent fasting (IF) can improve function and health during aging in laboratory model organisms, but the mechanisms at work await elucidation. We subjected fruit flies (Drosophila melanogaster) to varying degrees of IF and found that just one month of a 2-day fed:5-day fasted IF regime at the beginning of adulthood was sufficient to extend lifespan. This long-lasting, beneficial effect of early IF was not due to reduced fecundity. Starvation resistance and resistance to oxidative and xenobiotic stress were increased after IF. Early-life IF also led to higher lipid content in 60-day-old flies, a potential explanation for increased longevity. Guts of flies 40 days post-IF showed a significant reduction in age-related pathologies and improved gut barrier function. Improved gut health was also associated with reduced relative bacterial abundance. Early IF thus induced profound long-term changes. Pharmacological and genetic epistasis analysis showed that IF acted independently of the TOR pathway because rapamycin and IF acted additively to extend lifespan, and global expression of a constitutively active S6K did not attenuate the IF-induced lifespan extension. We conclude that short-term IF during early life can induce long-lasting beneficial effects, with robust increase in lifespan in a TOR-independent manner, probably at least in part by preserving gut health.


Subject(s)
Drosophila melanogaster/physiology , Food Deprivation , Longevity , Signal Transduction/genetics , Animals , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Feeding Behavior , Female , Gastrointestinal Tract/physiology , Male , Stress, Physiological , TOR Serine-Threonine Kinases/metabolism , Time Factors
4.
PLoS Biol ; 15(9): e2001655, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28902870

ABSTRACT

Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the "insulin paradox"). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.


Subject(s)
Aging/physiology , Drosophila/physiology , Insulin/metabolism , Somatomedins/metabolism , Synaptic Transmission , Animals , Connexins/metabolism , Escape Reaction/physiology , Female , Gap Junctions/physiology , Male , rab GTP-Binding Proteins/metabolism
5.
Development ; 144(13): 2445-2455, 2017 07 01.
Article in English | MEDLINE | ID: mdl-28533206

ABSTRACT

Growth factors of the TGFß superfamily play key roles in regulating neuronal and muscle function. Myostatin (or GDF8) and GDF11 are potent negative regulators of skeletal muscle mass. However, expression of myostatin and its cognate receptors in other tissues, including brain and peripheral nerves, suggests a potential wider biological role. Here, we show that Myoglianin (MYO), the Drosophila homolog of myostatin and GDF11, regulates not only body weight and muscle size, but also inhibits neuromuscular synapse strength and composition in a Smad2-dependent manner. Both myostatin and GDF11 affected synapse formation in isolated rat cortical neuron cultures, suggesting an effect on synaptogenesis beyond neuromuscular junctions. We also show that MYO acts in vivo to inhibit synaptic transmission between neurons in the escape response neural circuit of adult flies. Thus, these anti-myogenic proteins act as important inhibitors of synapse function and neuronal growth.


Subject(s)
Cell Shape , Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Myostatin/metabolism , Neurons/cytology , Neurons/metabolism , Synapses/metabolism , Transforming Growth Factor beta/metabolism , Animals , Body Weight , Down-Regulation/genetics , Drosophila melanogaster/cytology , Gene Silencing , Glycogen Synthase Kinase 3/metabolism , Growth Differentiation Factors/metabolism , Humans , Larva/metabolism , Muscle Cells/metabolism , Neuroglia/metabolism , Neuromuscular Junction/metabolism , Rats , Signal Transduction , Synaptic Transmission
7.
Curr Biol ; 26(17): 2291-300, 2016 09 12.
Article in English | MEDLINE | ID: mdl-27524482

ABSTRACT

Glucose hypometabolism is a prominent feature of the brains of patients with Alzheimer's disease (AD). Disease progression is associated with a reduction in glucose transporters in both neurons and endothelial cells of the blood-brain barrier. However, whether increasing glucose transport into either of these cell types offers therapeutic potential remains unknown. Using an adult-onset Drosophila model of Aß (amyloid beta) toxicity, we show that genetic overexpression of a glucose transporter, specifically in neurons, rescues lifespan, behavioral phenotypes, and neuronal morphology. This amelioration of Aß toxicity is associated with a reduction in the protein levels of the unfolded protein response (UPR) negative master regulator Grp78 and an increase in the UPR. We further demonstrate that genetic downregulation of Grp78 activity also protects against Aß toxicity, confirming a causal effect of its alteration on AD-related pathology. Metformin, a drug that stimulates glucose uptake in cells, mimicked these effects, with a concomitant reduction in Grp78 levels and rescue of the shortened lifespan and climbing defects of Aß-expressing flies. Our findings demonstrate a protective effect of increased neuronal uptake of glucose against Aß toxicity and highlight Grp78 as a novel therapeutic target for the treatment of AD.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/genetics , Drosophila melanogaster/physiology , Gene Expression , Glucose Transporter Type 1/metabolism , Hypoglycemic Agents/pharmacology , Metformin/pharmacology , Neurons/drug effects , Amyloid beta-Peptides/metabolism , Animals , Animals, Genetically Modified/genetics , Animals, Genetically Modified/physiology , Disease Models, Animal , Drosophila melanogaster/drug effects , Drosophila melanogaster/genetics , Endoplasmic Reticulum Chaperone BiP , Female , Glucose Transporter Type 1/genetics , Heat-Shock Proteins/metabolism , Neurons/physiology
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