Mitochondrial Quality Control in Alzheimer’s Disease: Insights from Caenorhabditis elegans Models DOI Creative Commons
Upasana Ganguly, Trae Carroll, Keith Nehrke

et al.

Antioxidants, Journal Year: 2024, Volume and Issue: 13(11), P. 1343 - 1343

Published: Nov. 1, 2024

Alzheimer's disease (AD) is a complex neurodegenerative disorder that classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and intracellular accumulation neurofibrillary tangles (NFTs) are aberrantly modified tau protein. In addition to aggregative proteostatic abnormalities, neurons affected AD also frequently possess dysfunctional mitochondria disrupted mitochondrial maintenance, such as inability eliminate damaged via mitophagy. Decades have been spent interrogating etiopathogenesis AD, contributions from model organism research aided developing more fundamental understanding molecular dysfunction caused Aβ toxic aggregates. The soil nematode

Language: Английский

The multiple links between actin and mitochondria DOI
Tak Shun Fung, Rajarshi Chakrabarti, Henry N. Higgs

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(9), P. 651 - 667

Published: June 5, 2023

Language: Английский

Citations

54
Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation DOI Creative Commons

Michael O. Isei,

Meredith Crockett,

Emily Chen

et al.

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0307358 - e0307358

Published: Jan. 3, 2025

Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer’s disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles selectively removed from the network. The precise mechanism this occurs remains unclear. Previously, we showed that has been mutated at Thr-231 to glutamic acid mimic an Alzheimer’s-relevant phospho-epitope expressed early in disease inhibits oxidative stress-induced mitophagy Caenorhabditis elegans . Here, use immortalized mouse hippocampal neuronal cell lines extend result into mammalian cells. Specifically, show phosphomimetic Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly induction paraquat, potent inducer of stress. Moreover, combination immunologic and biochemical approaches demonstrates levels receptor FKBP8, significantly decrease response paraquat cells expressing EC EM mutants, but not wildtype tau. contrast, treatment results receptors FUNDC1 BNIP3 presence both mutants. Interestingly, FKBP8 is normally trafficked endoplasmic reticulum during stress induced our support model where trafficking impacted disease-relevant tau, perhaps direct interaction. We provide new insights molecular mechanisms underlying pathology highlight as potential target for mitigating dysfunction neurodegenerative diseases.

Language: Английский

Citations

1
Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases DOI

Yuqi Fu,

Jin Zhang, Rui Qin

et al.

Pharmacological Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 100053 - 100053

Published: March 1, 2025

Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson Huntington amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due intricate pathogenesis substantial variability among patients, including differences in environmental exposures genetic predispositions. One of the defining characteristics NDs is widely reported be buildup misfolded proteins. For example, disease marked by amyloid beta hyperphosphorylated Tau aggregates, whereas exhibits α-synuclein aggregates. Amyotrophic sclerosis dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, fused-in sarcoma involves mutant huntingtin polyglutamine These proteins key biomarkers also serve potential therapeutic targets, they can addressed through autophagy, a process that removes excess cellular inclusions maintain homeostasis. Various forms macroautophagy, chaperone-mediated microautophagy, hold promise eliminating toxic implicated NDs. In this review, we focus on elucidating regulatory connections between autophagy NDs, summarizing cause exploring impact mechanisms, discussing how regulate aggregation. Moreover, underscore activation strategy across different small molecules capable activating pathways, rapamycin targeting mTOR pathway clear Sertraline AMPK/mTOR/RPS6KB1 Tau, further illustrate NDs' intervention. Together, these findings would provide new insights into current research trends propose small-molecule drugs promising strategies future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview eliminate aggregates neurodegenerative diseases. It elucidates fascinating interrelationships "chasing escaping" phenomenon. discusses progress utilizing activate improve efficacy therapies removing

Language: Английский

Citations

1
Mitochondrial mechanisms in the pathogenesis of chronic inflammatory musculoskeletal disorders DOI Creative Commons
Kailun Wu,

Ju-sheng Shieh,

Ling Qin

et al.

Cell & Bioscience, Journal Year: 2024, Volume and Issue: 14(1)

Published: June 8, 2024

Abstract Chronic inflammatory musculoskeletal disorders characterized by prolonged muscle inflammation, resulting in enduring pain and diminished functionality, pose significant challenges for the patients. Emerging scientific evidence points to mitochondrial malfunction as a pivotal factor contributing these ailments. Mitochondria play critical role powering skeletal activity, but context of persistent disruptions their quantity, configuration, performance have been well-documented. Various disturbances, encompassing alterations dynamics (such fission fusion), calcium regulation, oxidative stress, biogenesis, process mitophagy, are believed central progression disorders. Additionally, unfolded protein responses accumulation fatty acids within cells may adversely affect internal milieu, impairing equilibrium functioning. The structural discrepancies between different subsets namely, intramyofibrillar subsarcolemmal mitochondria likely impact metabolic capabilities susceptibility influences. release signals from damaged is known incite responses. Intriguingly, migrasomes extracellular vesicles serve vehicles intercellular transfer mitochondria, aiding removal impaired regulation inflammation. Viral infections implicated inducing stress on mitochondria. Prolonged dysfunction vital organelles sustains harm, irregularities, heightened cytokine release, impeding body’s ability repair tissues. This review provides comprehensive analysis advancements understanding changes intracellular environment, architecture distribution, dynamics, autophagy, cytokines associated with vesicular structures, membranes chronic Strategies targeting key elements regulating quality exhibit promise restoration function, alleviation enhancement overall outcomes. Graphical

Language: Английский

Citations

8
Drp1: Focus on Diseases Triggered by the Mitochondrial Pathway DOI

Fulin Sun,

Min Fang, Huhu Zhang

et al.

Cell Biochemistry and Biophysics, Journal Year: 2024, Volume and Issue: 82(2), P. 435 - 455

Published: March 4, 2024

Language: Английский

Citations

6
Studying the mechanisms of neurodegeneration: C. elegans advantages and opportunities DOI Creative Commons
Angie K. Torres, Rodrigo G. Mira,

Cristina Pinto

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: March 26, 2025

Caenorhabditis elegans has been widely used as a model organism in neurodevelopment for several decades due to its simplicity, rapid growth, short life cycle, transparency, and rather simple genetics. It useful modeling neurodegenerative diseases by the heterologous expression of major proteins that form neurodegenerative-linked aggregates such amyloid- β peptide, tau protein, α -synuclein, among others. Furthermore, chemical treatments well existence interference RNA libraries, transgenic worm lines, possibility generating new strains create magnificent range possible tools study signaling pathways could confer protection against protein or, on contrary, are playing detrimental role. In this review, we summarize different C. models with focus Alzheimer’s Parkinson’s how genetic be dissect involved their pathogenesis mentioning examples. Finally, discuss use pharmacological agents help these disease-associated powerful combinations experimental designs tools. This review highlights advantages valuable intermediary between vitro mammalian vivo development potential therapies.

Language: Английский

Citations

0
The mechanisms and roles of mitochondrial dynamics in C. elegans DOI Creative Commons
Daniel Campbell, Steven Zuryn

Seminars in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 156, P. 266 - 275

Published: Nov. 1, 2023

If mitochondria are the powerhouses of cell, then mitochondrial dynamics power grid that regulates how energy output is directed and maintained in response to unique physiological demands. Fission fusion highly regulated processes fine-tune networks cells enable appropriate responses intrinsic extrinsic stimuli, thereby maintaining cellular organismal homeostasis. These shape many aspects an organism's healthspan including development, longevity, stress resistance, immunity, disease. In this review, we discuss latest findings regarding mechanisms roles by focussing on nematode Caenorhabditis elegans. Whole live-animal studies C. elegans have enabled a true organismal-level understanding impact play homeostasis over lifetime.

Language: Английский

Citations

7
Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation DOI

Michael O. Isei,

Meredith Crockett,

Emily Chen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 9, 2024

Abstract Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer’s disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles selectively removed from the network. The precise mechanism this occurs remains unclear. Previously, we showed that has been mutated at Thr-231 to glutamic acid mimic an Alzheimer’s-relevant phospho-epitope expressed early in disease inhibits oxidative stress-induced mitophagy C. elegans . Here, use immortalized mouse hippocampal neuronal cell lines extend result into mammalian cells. Specifically, show phosphomimetic Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly induction paraquat, potent inducer of stress. Moreover, combination immunologic and biochemical approaches demonstrates levels receptor FKBP8, significantly decrease response paraquat cells expressing EC EM mutants, but not wildtype tau. contrast, treatment results receptors FUNDC1 BNIP3 presence both mutants. Interestingly, FKBP8 is normally trafficked endoplasmic reticulum during stress induced our support model where trafficking impacted disease-relevant tau, perhaps direct interaction. We provide new insights molecular mechanisms underlying pathology highlight as potential target for mitigating dysfunction neurodegenerative diseases.

Language: Английский

Citations

1
Mitochondrial Quality Control in Alzheimer’s Disease: Insights from Caenorhabditis elegans Models DOI Creative Commons
Upasana Ganguly, Trae Carroll, Keith Nehrke

et al.

Antioxidants, Journal Year: 2024, Volume and Issue: 13(11), P. 1343 - 1343

Published: Nov. 1, 2024

Alzheimer's disease (AD) is a complex neurodegenerative disorder that classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and intracellular accumulation neurofibrillary tangles (NFTs) are aberrantly modified tau protein. In addition to aggregative proteostatic abnormalities, neurons affected AD also frequently possess dysfunctional mitochondria disrupted mitochondrial maintenance, such as inability eliminate damaged via mitophagy. Decades have been spent interrogating etiopathogenesis AD, contributions from model organism research aided developing more fundamental understanding molecular dysfunction caused Aβ toxic aggregates. The soil nematode

Language: Английский

Citations

0