Defects of Nutrient Signaling and Autophagy in Neurodegeneration

Ondaro, Jon; Hernandez-Eguiazu, Haizea; Garciandia-Arcelus, Maddi; Loera-Valencia, Raúl; Rodriguez-Gómez, Laura; Jiménez-Zúñiga, Andrés; Goikolea, Julen; Rodriguez-Rodriguez, Patricia; Ruíz‐Martínez, Javier; Moreno, Fermín; Munáin, Adolfo López de; Holt, Ian; Gil-Bea, Francisco J.; Gereñu, Gorka

doi:10.3389/fcell.2022.836196

Cited by 10 publications

(5 citation statements)

References 368 publications

(446 reference statements)

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“…In fact, mitochondrial dysfunction is becoming a major contributor to the development of LSDs, and impaired mitophagy is a common mechanism that is shared by many of these disorders [43,71,75]. This suggests that the imbalance between lysosomal and mitochondrial functions caused by GRN insufficiency could represent a shared mechanism contributing to the onset of neurodegenerative conditions, as has already been proposed [24,61]. For instance, mutations that have been linked to several types of Charcot-Marie-Tooth syndrome, Parkinson's Disease, and LSDs, have been shown to disrupt the interactions between mitochondria and lysosomes [21].…”

Section: Discussionmentioning

confidence: 94%

“…The lysosome is a dynamic organelle that, through its role in cellular waste and recycling, is proficient in centrally regulating nutrient sensing and reconfiguring metabolism of the cell in response to energy demand, to maintain cellular homeostasis and ensure survival [61]. To fulfill this role, the lysosome interacts with other cellular structures exchanging content and information through establishing membrane contact sites [10].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, alterations at the lysosomal level have the potential to impact cellular homeostasis during periods of energy demand at least at two different levels: first, by impeding the availability of FAs as an alternative fuel source, and second, by increasing the risk of accumulating aberrant metabolic organelles such as mitochondria [61]. The latter may result in less flexibility to reconfigure alternative sources of energy production.…”

Section: Introductionmentioning

confidence: 99%

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Lipid Dysregulation Unveil the Intricate Interplay of Lysosomal and Mitochondrial Changes in Frontotemporal Dementia with GRN Haploinsufficiency

Ondaro,

Zúñiga-Elizari,

Zufiría

et al. 2024

Preprint

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This study investigates the cellular pathology resulting from haploinsufficiency of progranulin (PGRN) in frontotemporal dementia (FTD) associated with granulin (GRN) mutations. Utilizing fibroblasts from FTD patients carrying a distinctive GRN mutation (c.709-1G>A), we observed lysosomal and lipofuscin accumulation, impaired lysosomal function, compromised autophagic flux, and mitochondrial abnormalities. Notably, recombinant human progranulin (rhPGRN) treatment restored lysosomal acidification, mitigated mitochondrial defects, and demonstrated beneficial effects. FTD-GRN fibroblasts exhibited abnormal lipid metabolism with increased lipid droplet formation, influenced by GRN haploinsufficiency and modulated by rhPGRN. Under nutrient-rich conditions, lipid droplet dynamics were shaped by autophagy and mitochondrial processes, potentially due to impaired fatty acid oxidation. These findings highlight a direct association between GRN deficiency and altered lysosomal-mitochondrial interactions, influencing lipid metabolism and contributing to FTD pathogenesis. The documented lysosomal dysfunction, impaired autophagy, mitochondrial anomalies, and altered lipid metabolism collectively suggest a complex interplay of cellular processes in the development of FTD-GRN.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lipid Dysregulation Unveil the Intricate Interplay of Lysosomal and Mitochondrial Changes in Frontotemporal Dementia with GRN Haploinsufficiency

Ondaro,

Zúñiga-Elizari,

Zufiría

et al. 2024

Preprint

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“…In addition to the MET growth signaling, this study showed AMPK activation and increase of neurofibromin in amyloid-high areas. Activation of AMPK is a sign of autophagy pathway activation, which can antagonize amyloid toxicity [43]. Neurofibromin is a RAS-GAP, antagonizing RAS signaling activation, thus function as tumor suppressor [21].…”

Section: Discussionmentioning

confidence: 99%

The MET growth signaling complex drives Alzheimer’s Disease-associated brain pathology in aged Shugoshin 1 mouse cohesinopathy model

Rao,

Crane,

Fowler

et al. 2024

Preprint

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The understanding on molecular processes toward Late-onset Alzheimers Disease (LOAD) has been insufficient to design LOAD intervention drugs. Previously, we discovered transgenic genomic instability model mice Sgo1-/+ accumulate cerebral amyloid-beta in old age. We pro-posed the amyloid-beta accumulation cycle hypothesis, in which cytotoxic, mitogenic and aneuploidgenic amyloid can create an autonomous mitotic cycle leading to accumulation of itself. However, the nature of the growth signaling that drives cells toward pathogenic mitotic cycle remained unidentified. In this study, we hypothesized that the aged Sgo1-/+ mice brains would show signs of mitogenic signaling activation, and searched for growth signaling activated in the vicinity of amyloid-beta, with spatial analysis on the cortex and hippocampus of Sgo1-/+ mice in middle-age and old-age. The analysis indicated activations of kinase signaling p42/44 MAPK ERK1/2, AMPK, JNK, Wnt signaling via GSK3 inactivation, as well as increases of p-TAU and other AD biomarkers, PLCG1, EGFR, MET, Neurofibromin and RAS. Immune activation markers CD45 and CD31 were also elevated in the microenvironment. A majority of activated growth signaling components are of the oncogenic MET signaling complex. The discovery supports re-purposing of cancer drugs targeting the MET signaling complex and EGFR-RAS-MAPK axis for intervention and/or treatment of genomic instability-driven AD.

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“…In parallel, ageing is also regulated by metabolic mechanisms. Nutrient signalling regulates ageing and age-related neurodegeneration [ 71 ] via the signalling pathways of the growth hormone (GH)/insulin-like growth factor (IGF), the mechanistic target of rapamycin (mTOR), sirtuins, and 5' AMP-activated protein kinase (AMPK) [ 72 , 73 ].…”

Section: Molecular Mechanisms Of Brain Ageingmentioning

confidence: 99%

Ageing in the brain: mechanisms and rejuvenating strategies

Gaspar-Silva

Trigo

Magalhaes

2023

Cell. Mol. Life Sci.

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Ageing is characterized by the progressive loss of cellular homeostasis, leading to an overall decline of the organism’s fitness. In the brain, ageing is highly associated with cognitive decline and neurodegenerative diseases. With the rise in life expectancy, characterizing the brain ageing process becomes fundamental for developing therapeutic interventions against the increased incidence of age-related neurodegenerative diseases and to aim for an increase in human life span and, more importantly, health span. In this review, we start by introducing the molecular/cellular hallmarks associated with brain ageing and their impact on brain cell populations. Subsequently, we assess emerging evidence on how systemic ageing translates into brain ageing. Finally, we revisit the mainstream and the novel rejuvenating strategies, discussing the most successful ones in delaying brain ageing and related diseases.

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Defects of Nutrient Signaling and Autophagy in Neurodegeneration

Abstract: Graphical AbstractSchematic Representation Highlighting the Mechanisms of Nutrient Sensing and Autophagy Under Physiological Conditions.

Cited by 10 publications

References 368 publications

Lipid Dysregulation Unveil the Intricate Interplay of Lysosomal and Mitochondrial Changes in Frontotemporal Dementia with GRN Haploinsufficiency

Lipid Dysregulation Unveil the Intricate Interplay of Lysosomal and Mitochondrial Changes in Frontotemporal Dementia with GRN Haploinsufficiency

The MET growth signaling complex drives Alzheimer’s Disease-associated brain pathology in aged Shugoshin 1 mouse cohesinopathy model

Ageing in the brain: mechanisms and rejuvenating strategies

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