Role of autophagy and proteostasis in neurodegenerative diseases: Exploring the therapeutic interventions DOI
Surbhi Panwar,

Prerna Uniyal,

Neelima Kukreti

et al.

Chemical Biology & Drug Design, Journal Year: 2024, Volume and Issue: 103(4)

Published: April 1, 2024

Abstract Neurodegenerative disorders are devastating characterized by gradual loss of neurons and cognition or mobility impairment. The common pathological features these diseases associated with the accumulation misfolded aggregation proteins. pivotal roles autophagy proteostasis in maintaining cellular health preventing proteins, which neurodegenerative like Huntington's disease (HD), Alzheimer's (AD), Parkinson's (PD). This article presents an in‐depth examination interplay between proteostasis, highlighting how processes cooperatively contribute to homeostasis prevent pathogenic protein aggregate accumulation. Furthermore, review emphasises potential therapeutic implications targeting mitigate diseases. While advancements research hold promise for developing novel treatments, also addresses challenges complexities modulating intricate pathways. Ultimately, advancing understanding underlying mechanism provides valuable insights into avenues future directions.

Language: Английский

Hallmarks of neurodegenerative diseases DOI Creative Commons

David M. Wilson,

Mark Cookson, Ludo Van Den Bosch

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(4), P. 693 - 714

Published: Feb. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Language: Английский

Citations

801
The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing DOI Creative Commons
Yuqing Liu, Yejun Tan, Zheyu Zhang

et al.

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Jan. 23, 2024

Abstract Ageing is a crucial risk factor for Alzheimer’s disease (AD) and characterised by systemic changes in both intracellular extracellular microenvironments that affect the entire body instead of single organ. Understanding specific mechanisms underlying role ageing development can facilitate treatment ageing-related diseases, such as AD. Signs brain have been observed AD patients animal models. Alleviating pathological caused dramatically ameliorate amyloid beta- tau-induced neuropathological memory impairments, indicating plays pathophysiological process In this review, we summarize impact several age-related factors on propose preventing promising strategy improving cognitive health.

Language: Английский

Citations

30
Redox regulation: mechanisms, biology and therapeutic targets in diseases DOI Creative Commons
Bowen Li, Hui Ming, Siyuan Qin

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Language: Английский

Citations

4
Stress dynamically modulates neuronal autophagy to gate depression onset DOI Creative Commons
Liang Yang, Guo Chen, Zhi-Wei Zheng

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders1. As a key modulator of homeostasis2, it remains elusive whether and how autophagy is engaged dynamics. Here we discover that acute activates, whereas chronic suppresses, mainly the lateral habenula (LHb). Systemic administration distinct antidepressant drugs similarly restores function LHb, suggesting LHb as common target. Genetic ablation neuronal promotes susceptibility, enhancing exerts rapid antidepressant-like effects. controls excitability, synaptic transmission plasticity by means on-demand degradation glutamate receptors. Collectively, this study shows causal role maintaining emotional homeostasis against stress. Disrupted implicated maladaptation stress, its reversal enhancers provides new strategy.

Language: Английский

Citations

2
Oligodendroglial macroautophagy is essential for myelin sheath turnover to prevent neurodegeneration and death DOI Creative Commons

Etan R. Aber,

Christopher J. Griffey, Tim Davies

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 41(3), P. 111480 - 111480

Published: Oct. 1, 2022

Although macroautophagy deficits are implicated across adult-onset neurodegenerative diseases, we understand little about how the discrete, highly evolved cell types of central nervous system use to maintain homeostasis. One such type is oligodendrocyte, whose myelin sheaths for reliable conduction action potentials. Using an integrated approach mouse genetics, live imaging, electron microscopy, and biochemistry, show that mature oligodendrocytes require degrade autonomously their by consolidating cytosolic transmembrane proteins into amphisome intermediate prior degradation. We find disruption autophagic turnover leads changes in sheath structure, ultimately impairing neural function culminating progressive motor decline, neurodegeneration, death. Our model indicates continuous cell-autonomous maintenance through essential, shedding insight dysregulation might contribute disease pathophysiology.

Language: Английский

Citations

39
Protein homeostasis in aging and cancer DOI Creative Commons

Xiao‐Qiong Chen,

Tao Shen, Shaojun Fang

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Feb. 16, 2023

Aging is a major risk factor for cancer development. As dysfunction in protein homeostasis, or proteostasis, universal hallmark of both the aging process and cancer, comprehensive understanding proteostasis system its roles will shed new light on how we can improve health quality life older individuals. In this review, summarize regulatory mechanisms discuss relationship between age-related diseases, including cancer. Furthermore, highlight clinical application value maintenance delaying promoting long-term health.

Language: Английский

Citations

26
Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease DOI Open Access
Kamil Saramowicz, Natalia Siwecka, Grzegorz Galita

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 25(1), P. 360 - 360

Published: Dec. 26, 2023

Parkinson’s disease (PD) is a complex neurodegenerative characterized by the progressive loss of dopaminergic neurons in substantia nigra and widespread accumulation alpha-synuclein (αSyn) protein aggregates. αSyn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, proteostasis, which culminate neuronal cell death. Importantly, pathology extends beyond neurons—it also encompasses spreading throughout environment internalization microglia astrocytes. Once internalized, glia can act as neuroprotective scavengers, limit spread αSyn. However, they become reactive, thereby contributing to neuroinflammation progression PD. Recent advances research have enabled molecular diagnosis PD accelerated development targeted therapies. Nevertheless, despite more than two decades research, mechanisms, induction damage remain incompletely understood. Unraveling interplay between αSyn, neurons, may provide insights into initiation progression, bring us closer exploring new effective therapeutic strategies. Herein, we an overview recent studies emphasizing multifaceted nature its impact on both neuron glial damage.

Language: Английский

Citations

23
The protective role of baicalin regulation of autophagy in cancers DOI Creative Commons
Qí Zhāng,

Shiyun Guo,

Han Ge

et al.

Cytotechnology, Journal Year: 2025, Volume and Issue: 77(1)

Published: Jan. 3, 2025

Language: Английский

Citations

1
Decoding the role of large heat shock proteins in the progression of neuroinflammation‐mediated neurodegenerative disorders DOI Creative Commons
Shailendra K. Saxena, Deepak Sharma,

Swatantra Kumar

et al.

Neuroprotection/Neuroprotection (Chichester, England. Print), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Abstract Chronic neuroinflammation and protein aggregation are the fundamental events mainly responsible for progression of neurodegenerative diseases (NDs). Potential neurotoxic changes in intra‐ extracellular environment typical hallmarks many NDs. Treatment ND is challenging, as symptoms these patients arises when a significant numbers neurons have already been destroyed. Heat shock proteins (HSPs) can bind to recipient cells that susceptible stress, such neurons, environment, therefore enhancing stress resistance. Among all, HSP60, HSP70, HSP90 highly conserved molecular chaperones involved folding assembly, maintaining cellular homeostasis central nervous system. Notably, α‐synuclein accumulation major pathophysiology Parkinson's disease, where modulates assembly vesicles prevent its accumulation. Moreover, regulates activity glycogen synthase kinase‐3β protein, which crucial diabetes mellitus‐associated neurocognitive disorder. Therefore, understanding mechanism by HSPs facilitate respond inflammatory stimuli, including metabolic disease diabetes, essential significance This review emphasizes role various NDs Alzheimer's, Parkinson's, multiple sclerosis, Huntington's one risk factors neurodegeneration.

Language: Английский

Citations

1
WTAP suppresses STAT3 via m6A methylation to regulate autophagy and inflammation in central nervous system injury DOI Creative Commons
Xiaoyong Zhao, Xiaoli Zhang, Liangzhi Wu

et al.

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106811 - 106811

Published: Jan. 1, 2025

Language: Английский

Citations

1