scholarly journals AMPK Modulates Associative Learning via Neuronal Mitochondrial Fusion in C. elegans

2020 ◽  
Author(s):  
Caroline C. Escoubas ◽  
Vanessa Laversenne ◽  
Emina Tabakovic ◽  
Heather J. Weir ◽  
Nicole Clark ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Associative Learning ◽  
Therapeutic Option ◽  
Mitochondrial Fusion ◽  
Ampk Activation ◽  
Neuronal Function ◽  
Learning Capacity ◽  
C Elegans ◽  
Mitochondrial Homeostasis ◽  
Age Related

ABSTRACTLoss of metabolic homeostasis is one of the hallmarks of the aging process that might contribute to pathogenesis by creating a permissive landscape over which neurodegenerative diseases can take hold. AMPK, a conserved energy sensor, extends lifespan and is protective in some neurodegenerative models. AMPK regulates mitochondrial homeostasis and morphology, however, whether mitochondrial regulation causally links AMPK to protection against loss of neuronal function with aging and diseases remains unclear. Here we use an associative learning protocol in C. elegans as a readout of neuronal function and show that AMPK activation enhances associative learning and prevents age-related loss of learning capacity. AMPK promotes neuronal mitochondrial fusion and mitochondrial fragmentation via fzo-1 deletion blocks AMPK’s effects on associative learning. Restoring mitochondrial fusion capacity specifically in the neurons rescued learning capacity downstream of AMPK. Finally, AMPK activation rescues neuronal Aβ1-42 induced loss of associative learning. Overall, our results suggest that targeting neuronal metabolic flexibility may be a viable therapeutic option to restore neuronal function in the context of aging and neurodegenerative diseases.

scholarly journals Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 163
Author(s):  
Swapnil Gupta ◽  
Panpan You ◽  
Tanima SenGupta ◽  
Hilde Nilsen ◽  
Kulbhushan Sharma
Keyword(s):  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
3D Models ◽  
Model Systems ◽  
Spinocerebellar Ataxias ◽  
C Elegans ◽  
Cellular Processes ◽  
Age Related ◽  
Damage Response ◽  
Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

scholarly journals C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1188 ◽  
Author(s):  
Carl Alexander Sandhof ◽  
Simon Oliver Hoppe ◽  
Jessica Tittelmeier ◽  
Carmen Nussbaum-Krammer
Keyword(s):  
Neurodegenerative Diseases ◽  
Model Organism ◽  
Model Systems ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Population Demographics ◽  
C Elegans ◽  
Age Related ◽  
Bona Fide ◽  
High Degree

A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites to interconnected brain areas is reminiscent of the behavior of bona fide prions in transmissible spongiform encephalopathies (TSEs), hence the term prion-like proteins has been coined. Despite intensive research, the exact mechanisms that facilitate the spreading of protein aggregation between cells, and the associated loss of neurons, remain poorly understood. As population demographics in many countries continue to shift to higher life expectancy, the incidence of neurodegenerative diseases is also rising. This represents a major challenge for healthcare systems and patients’ families, since patients require extensive support over several years and there is still no therapy to cure or stop these diseases. The model organism Caenorhabditis elegans offers unique opportunities to accelerate research and drug development due to its genetic amenability, its transparency, and the high degree of conservation of molecular pathways. Here, we will review how recent studies that utilize this soil dwelling nematode have proceeded to investigate the propagation and intercellular transmission of prions and prion-like proteins and discuss their relevance by comparing their findings to observations in other model systems and patients.

scholarly journals Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elissa Tjahjono ◽  
Jingqi Pei ◽  
Alexey V. Revtovich ◽  
Terri-Jeanne E. Liu ◽  
Alisha Swadi ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Small Molecules ◽  
Protein A ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Atp Production ◽  
C Elegans ◽  
Mitochondrial Homeostasis ◽  
Phenotypic Screen ◽  
Common Causes

AbstractMacroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of PINK1 and Parkin, two key regulators of mitophagy, are amongst the most common causes of heritable parkinsonism. This has led to the hypothesis that pharmacological stimulation of mitophagy may be a feasible approach to combat neurodegeneration. Toward this end, we screened ~ 45,000 small molecules using a high-throughput, whole-organism, phenotypic screen that monitored accumulation of PINK-1 protein, a key event in mitophagic activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes, including delaying paralysis in a C. elegans β-amyloid aggregation model in a PINK-1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover.

scholarly journals OPA1 deficiency accelerates hippocampal synaptic remodelling and age-related deficits in learning and memory

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Ryan J Bevan ◽  
Pete A Williams ◽  
Caroline T Waters ◽  
Rebecca Thirgood ◽  
Amanda Mui ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Memory Performance ◽  
Memory Deficits ◽  
Metabolic Dysfunction ◽  
Neuronal Function ◽  
Synaptic Density ◽  
Ca1 Neurons ◽  
Mitochondrial Homeostasis ◽  
Age Related ◽  
Spatial Novelty

Abstract A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerative events. To explore this, we quantified hippocampal dendritic and synaptic integrity and the learning and memory performance of aged Opa1 haploinsufficient mice carrying the Opa1Q285X mutation (B6; C3-Opa1Q285STOP; Opa1+/−). We demonstrate that heterozygous loss of Opa1 results in premature age-related loss of spines in hippocampal pyramidal CA1 neurons and a reduction in synaptic density in the hippocampus. This loss is associated with subtle memory deficits in both spatial novelty and object recognition. We hypothesize that metabolic failure to maintain normal neuronal activity at the level of a single spine leads to premature age-related memory deficits. These results highlight the importance of mitochondrial homeostasis for maintenance of neuronal function during ageing.

scholarly journals Metformin extends C. elegans lifespan through lysosomal pathway

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jie Chen ◽  
Yuhui Ou ◽  
Yi Li ◽  
Shumei Hu ◽  
Li-Wa Shao ◽  
...  
Keyword(s):  
Ampk Activation ◽  
First Line ◽  
Therapeutic Application ◽  
C Elegans ◽  
Age Related ◽  
In Vitro Reconstitution ◽  
Line Drug ◽  
Extension Effect

Metformin, a widely used first-line drug for treatment of type 2 diabetes (T2D), has been shown to extend lifespan and delay the onset of age-related diseases. However, its primary locus of action remains unclear. Using a pure in vitro reconstitution system, we demonstrate that metformin acts through the v-ATPase-Ragulator lysosomal pathway to coordinate mTORC1 and AMPK, two hubs governing metabolic programs. We further show in Caenorhabditis elegans that both v-ATPase-mediated TORC1 inhibition and v-ATPase-AXIN/LKB1-mediated AMPK activation contribute to the lifespan extension effect of metformin. Elucidating the molecular mechanism of metformin regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age-related diseases.

scholarly journals Trigonelline Extends the Lifespan of C. Elegans and Delays the Progression of Age-Related Diseases by Activating AMPK, DAF-16, and HSF-1

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Wen-Yu Zeng ◽  
Lin Tan ◽  
Cong Han ◽  
Zhuo-Ya Zheng ◽  
Gui-Sheng Wu ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Neurodegenerative Diseases ◽  
Stress Resistance ◽  
Aging Effect ◽  
Loss Of Function ◽  
Asian Countries ◽  
C Elegans ◽  
Age Related ◽  
Anti Oxidant ◽  
Pathogenic Effects

Trigonelline is the main alkaloid with bioactivity presented in fenugreek, which was used in traditional medicine in Asian countries for centuries. It is reported that trigonelline has anti-inflammatory, anti-oxidant, and anti-pathogenic effects. We are wondering whether trigonelline have anti-aging effect. We found that 50 μM of trigonelline had the best anti-aging activity and could prolong the lifespan of Caenorhabditis elegans (C. elegans) by about 17.9%. Trigonelline can enhance the oxidative, heat, and pathogenic stress resistance of C. elegans. Trigonelline could also delay the development of neurodegenerative diseases, such as AD, PD, and HD, in models of C. elegans. Trigonelline could not prolong the lifespan of long-lived worms with loss-of-function mutations in genes regulating energy and nutrition, such as clk-1, isp-1, eat-2, and rsks-1. Trigonelline requires daf-16, hsf-1, and aak-2 to extend the lifespan of C. elegans. Trigonelline can also up-regulate the expression of daf-16 and hsf-1 targeted downstream genes, such as sod-3, gst-4, hsp-16.1, and hsp-12.6. Our results can be the basis for developing trigonelline-rich products with health benefits, as well as for further research on the pharmacological usage of trigonelline.

scholarly journals Single-nucleus transcriptomic landscape of primate hippocampal aging

2021 ◽  
Author(s):  
Hui Zhang ◽  
Jiaming Li ◽  
Jie Ren ◽  
Shuhui Sun ◽  
Shuai Ma ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Aging Effects ◽  
Neuronal Function ◽  
Diagnostic Biomarkers ◽  
Age Related ◽  
Gene Expression Dynamics ◽  
Single Nucleus

AbstractThe hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

Autophagy and ageing: implications for age-related neurodegenerative diseases

2013 ◽  
Vol 55 ◽  
pp. 119-131 ◽  
Author(s):  
Bernadette Carroll ◽  
Graeme Hewitt ◽  
Viktor I. Korolchuk
Keyword(s):  
Neurodegenerative Diseases ◽  
Energy Availability ◽  
Future Studies ◽  
Intracellular Degradation ◽  
Age Related ◽  
Autophagy Induction ◽  
Social Importance ◽  
Cellular Dysfunction ◽  
Autophagy Activity ◽  
Intense Research

Autophagy is a process of lysosome-dependent intracellular degradation that participates in the liberation of resources including amino acids and energy to maintain homoeostasis. Autophagy is particularly important in stress conditions such as nutrient starvation and any perturbation in the ability of the cell to activate or regulate autophagy can lead to cellular dysfunction and disease. An area of intense research interest is the role and indeed the fate of autophagy during cellular and organismal ageing. Age-related disorders are associated with increased cellular stress and assault including DNA damage, reduced energy availability, protein aggregation and accumulation of damaged organelles. A reduction in autophagy activity has been observed in a number of ageing models and its up-regulation via pharmacological and genetic methods can alleviate age-related pathologies. In particular, autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Indeed, in certain situations, reduced autophagosome induction may actually provide benefits to ageing cells. Future studies will undoubtedly improve our understanding of exactly how the multiple signals that are integrated to control appropriate autophagy activity change during ageing, what affect this has on autophagy and to what extent autophagy contributes to age-associated pathologies. Identification of mechanisms that influence a healthy lifespan is of economic, medical and social importance in our ‘ageing’ world.

scholarly journals Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Priyanka Joshi ◽  
Michele Perni ◽  
Ryan Limbocker ◽  
Benedetta Mannini ◽  
Sam Casford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unfolded Protein Response ◽  
Neurodegenerative Disorders ◽  
C Elegans ◽  
Unfolded Protein ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Parkinson’S Diseases ◽  
Protein Response

AbstractAge-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 extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, 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 Alzheimer’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 neurodegenerative disorders.

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