Intra-mitochondrial proteostasis is directly coupled to alpha-synuclein and Amyloid β 1-42 pathology

Lautenschlaeger, Janin; Wagner-Valladolid, Sara; Stephens, Amberley D.; Fernández-Villegas, Ana; Hockings, Colin; Mishra, Ajay; Manton, James D.; Fantham, Marcus; Lü, Meng; Rees, Eric; Kaminski, Clemens F.; Schierle, Gabriele S Kaminski

doi:10.1101/561134

Cited by 3 publications

(1 citation statement)

References 88 publications

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“…7,8 It interferes the proton gradient across the electron transport chain (ETC), thereby disrupting adenosine triphosphate (ATP) synthesis. A recent study by Lautenschläger et al 9 has found that the addition of FCCP leads to greater intracellular Aβ42 aggregation in a HEK293T cell model. As mitochondria are the power source of the cell, it is unsurprising that oxidative stress incurred in the presence of Aβ42 aggregation could lead to changes in its metabolism, and hence to the overall energetics of the cell.…”

Section: Introductionmentioning

confidence: 98%

Intracellular Aβ42 aggregation leads to cellular thermogenesis

Chung¹,

Stephens²,

Konno

et al. 2022

Preprint

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The aggregation of Aβ42 is a hallmark of Alzheimer′s disease. It is still not known what the biochemical changes are inside a cell which will eventually lead to Aβ42 aggregation. Thermogenesis has been associated with cellular stress, the latter of which may promote aggregation. We perform intracellular thermometry measurements using fluorescent polymeric thermometers (FPTs) to show that Aβ42 aggregation in live cells leads to an increase in cell-averaged temperatures. This rise in temperature is mitigated upon treatment with an aggregation inhibitor of Aβ42 and is independent of mitochondrial damage that can otherwise lead to thermogenesis. With this, we present a diagnostic assay which could be used to screen small-molecule inhibitors to amyloid proteins in physiologically relevant settings. To interpret our experimental observations and motivate the development of future models, we perform classical molecular dynamics of model Aβ peptides to examine the factors that hinder thermal dissipation. We observe that this is controlled by the presence of ions in its surrounding environment, the morphology of the amyloid peptides and the extent of its hydrogen-bonding interactions with water. We show that aggregation and heat retention by Aβ peptides are favoured under intracellular-mimicking ionic conditions, which could potentially promote thermogenesis. The latter will, in turn, trigger further nucleation events that accelerate disease progression.

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Section: Introductionmentioning

confidence: 98%

Intracellular Aβ42 aggregation leads to cellular thermogenesis

Chung¹,

Stephens²,

Konno

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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A Propagated Skeleton Approach to High Throughput Screening of Neurite Outgrowth for In Vitro Parkinson’s Disease Modelling

Schikora

Kiwatrowski

Förster

et al. 2021

Cells

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Neuronal models of neurodegenerative diseases such as Parkinson’s Disease (PD) are extensively studied in pathological and therapeutical research with neurite outgrowth being a core feature. Screening of neurite outgrowth enables characterization of various stimuli and therapeutic effects after lesion. In this study, we describe an autonomous computational assay for a high throughput skeletonization approach allowing for quantification of neurite outgrowth in large data sets from fluorescence microscopic imaging. Development and validation of the assay was conducted with differentiated SH-SY5Y cells and primary mesencephalic dopaminergic neurons (MDN) treated with the neurotoxic lesioning compound Rotenone. Results of manual annotation using NeuronJ and automated data were shown to correlate strongly (R2-value 0.9077 for SH-SY5Y cells and R2-value 0.9297 for MDN). Pooled linear regressions of results from SH-SY5Y cell image data could be integrated into an equation formula (y=0.5410·x+1792; y=0.8789·x+0.09191 for normalized results) with y depicting automated and x depicting manual data. This automated neurite length algorithm constitutes a valuable tool for modelling of neurite outgrowth that can be easily applied to evaluate therapeutic compounds with high throughput approaches.

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A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

Burtscher

Maglione

Pardo

et al. 2021

IJMS

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Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings. Here, we discuss the potential of more holistic approaches with the purpose to re-establish a healthy cellular environment and to promote cellular resilience. We review the involvement of important molecular pathways (e.g., the sphingosine, δ-opioid receptor or N-Methyl-D-aspartate (NMDA) receptor pathways) in neuroprotective hypoxic conditioning effects and how these pathways can be targeted for chemical conditioning. Despite the present scarcity of knowledge on the efficacy of such approaches in neurodegeneration, the specific characteristics of Huntington’s disease may make it particularly amenable for such conditioning techniques. Not only do classical features of neurodegenerative diseases like mitochondrial dysfunction, oxidative stress and inflammation support this assumption, but also specific Huntington’s disease characteristics: a relatively young age of neurodegeneration, molecular overlap of related pathologies with hypoxic adaptations and sensitivity to brain hypoxia. The aim of this review is to discuss several molecular pathways in relation to hypoxic adaptations that have potential as drug targets in neurodegenerative diseases. We will extract the relevance for Huntington’s disease from this knowledge base.

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Intra-mitochondrial proteostasis is directly coupled to alpha-synuclein and Amyloid β 1-42 pathology

Cited by 3 publications

References 88 publications

Intracellular Aβ42 aggregation leads to cellular thermogenesis

Intracellular Aβ42 aggregation leads to cellular thermogenesis

A Propagated Skeleton Approach to High Throughput Screening of Neurite Outgrowth for In Vitro Parkinson’s Disease Modelling

A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

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