Lysosomal dysfunction in neurodegeneration: emerging concepts and methods

Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 45(3), P. 184 - 199

Published: Jan. 13, 2022

Language: Английский

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Impairment of the autophagy–lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential

Acta Pharmaceutica Sinica B, Journal Year: 2022, Volume and Issue: 12(3), P. 1019 - 1040

Published: Jan. 21, 2022

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (Aβ) peptides microtubule associated tau (MAPT/tau) in neuronal cells are hallmarks AD. So far, exact underlying mechanisms for aetiologies AD have not been fully understood effective treatment limited. Autophagy an evolutionarily conserved cellular catabolic process which damaged organelles degraded via lysosomes. Recently, there accumulating evidence linking impairment autophagy-lysosomal pathway with pathogenesis. Interestingly, enhancement autophagy to remove has proposed as a promising therapeutic strategy Here, we first summarize recent genetic, pathological experimental studies regarding We then describe interplay between two proteins, Aβ MAPT/tau, Finally, discuss potential strategies small molecules that target both animal models clinical trials. Overall, this article highlights pivotal functions pathogenesis druggable targets treatment.

Language: Английский

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The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy

Cell Reports, Journal Year: 2023, Volume and Issue: 42(2), P. 112037 - 112037

Published: Jan. 26, 2023

In response to lysosomal damage, cells engage several quality-control mechanisms, including the selective isolation and degradation of damaged lysosomes by lysophagy. Here, we report that autophagy adaptor SQSTM1/p62 is recruited in both HeLa neurons required for lysophagic flux. The Phox Bem1p (PB1) domain p62 mediates oligomerization specifically Consistent with this observation, find forms condensates on lysosomes. These are precisely tuned small heat shock protein HSP27, which phosphorylated injury maintains liquidity condensates, facilitating autophagosome formation. Mutations have been identified patients amyotrophic lateral sclerosis (ALS); ALS-associated mutations impair lysophagy, suggesting deficits pathway may contribute neurodegeneration. Thus, regulated HSP27 promote lysophagy forming platforms biogenesis at

Language: Английский

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STING trafficking as a new dimension of immune signaling

The Journal of Experimental Medicine, Journal Year: 2023, Volume and Issue: 220(3)

Published: Jan. 13, 2023

The cGAS-STING pathway is an evolutionarily conserved immune signaling critical for microbial defense. Unlike other innate pathways that largely rely on stationary cascades of events, STING highly mobile in the cell. activated ER, but only signals after it arrives Golgi, and then quickly degraded by lysosome. Each step trafficking through secretory regulated host factors. Homeostatic via COPI-, COPII-, clathrin-coated vesicles important maintaining baseline tissue cellular immunity. Aberrant vesicular or lysosomal dysfunction produces signal STING, which often leads to pathology mice humans. Many trafficking-mediated diseases appear impact central nervous system, leading neurodegeneration. Therefore, introduces a new dimension likely has broad implications human disease.

Language: Английский

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Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: June 8, 2023

Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have linked to lysosomal de-acidification through impairing vacuolar-type ATPase ion channels on organelle membrane. Similar abnormalities are also present sporadic forms neurodegeneration, although underlying pathogenic mechanisms unclear remain be investigated. Importantly, recent studies revealed early occurrence impairment before onset neurodegeneration late-stage pathology. However, there is lack methods for pH monitoring vivo dearth lysosome-acidifying therapeutic agents. Here, we summarize evidence notion defective an indicator urge critical need technological advancement developing tools detection both clinical applications. We further discuss current preclinical pharmacological agents that modulate acidification, small molecules nanomedicine, their potential translation into lysosome-targeting therapies. Both timely development therapeutics restore function represent paradigm shifts targeting diseases.

Language: Английский

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Shared genetic risk loci between Alzheimer’s disease and related dementias, Parkinson’s disease, and amyotrophic lateral sclerosis

Alzheimer s Research & Therapy, Journal Year: 2023, Volume and Issue: 15(1)

Published: June 16, 2023

Genome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's (PD) amyotrophic lateral sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific variants loci underlying this remain almost entirely unknown.

Language: Английский

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Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 7, 2025

Aspirin is a potent lysine acetylation inducer, but its impact on ubiquitination and ubiquitination-directed protein degradation unclear. Herein, we develop the reversed-pulsed-SILAC strategy to systematically profile degradome in response aspirin. By integrating degradome, acetylome, ubiquitinome analyses, show that aspirin impairs proteasome activity inhibit proteasomal degradation, rather than directly suppressing ubiquitination. Interestingly, increases lysosomal degradation-implicated K63-linked Accordingly, using major pathological of Parkinson's disease (PD), α-synuclein (α-syn), as an example aggregates, find able reduce α-syn cultured cells, neurons, PD model mice with rescued locomotor ability. We further reveal aggregate clearance induced by K63-ubiquitination dependent both cells mice. These findings suggest two complementary mechanisms which regulates soluble insoluble proteins, providing insights into diverse pharmacological effects can aid future drug development efforts.

Language: Английский

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Fluorescent probes for imaging bioactive species in subcellular organelles

Chemical Communications, Journal Year: 2021, Volume and Issue: 57(91), P. 12058 - 12073

Published: Jan. 1, 2021

Luminescent molecular probes and nanoscale materials have become important tools in biosensing bioimaging applications because of their high sensitivity, fast response, specificity, methodological simplicity.

Language: Английский

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Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency

The EMBO Journal, Journal Year: 2022, Volume and Issue: 41(4)

Published: Jan. 12, 2022

Haploinsufficiency of the progranulin (PGRN)‐encoding gene (GRN) causes frontotemporal lobar degeneration (GRN‐FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, TDP‐43 deposition. To understand contribution hyperactivation to pathology, we used genetic pharmacological approaches suppress TREM2‐dependent transition microglia from a homeostatic disease‐associated state. Trem2 deficiency Grn KO mice reduced hyperactivation. explore antibody‐mediated modulation states, identified antagonistic antibodies. Treatment macrophages GRN‐FTLD patients with these antibodies led signaling due its enhanced shedding. Furthermore, antibody‐treated PGRN‐deficient derived human‐induced pluripotent stem cells showed signaling, phagocytic activity, but dysfunction was not rescued. Similarly, lipid dysregulation, glucose hypometabolism were rescued by ablation. Synaptic loss neurofilament light‐chain (NfL) levels, biomarker for neurodegeneration, further elevated Grn/Trem2 cerebrospinal fluid (CSF). These findings suggest that models GRN does promote neurotoxicity, rather neuroprotection.

Language: Английский

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Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(5), P. 2400 - 2400

Published: Feb. 22, 2022

Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis eventual death. ALS has multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal deterioration viruses. This complexity major obstacle in defeating ALS. At present, riluzole edaravone are the only drugs that have passed clinical trials for treatment of ALS, notwithstanding they showed modest benefits limited population A dextromethorphan hydrobromide quinidine sulfate combination was also approved treat pseudobulbar affect (PBA) course Globally, there struggle prevent or alleviate symptoms this disease, implementation antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) ALS-on-a-chip technology. Additionally, researchers synthesized screened new compounds be effective beyond drug repurposing strategy. Despite all these efforts, largely palliative care, strong need therapeutics developed. review focuses on discusses therapeutic strategies been followed so far what can done future

Language: Английский

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