Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases DOI Creative Commons
Siwei Chu,

Xinyi Xie,

Carla Payan

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Aug. 7, 2023

Abstract The AAA + ATPase valosin containing protein (VCP) is essential for cell and organ homeostasis, especially in cells of the nervous system. As part a large network, VCP collaborates with many cofactors to ensure proteostasis under normal, stress, disease conditions. A number mutations have revealed importance human health. In particular, facilitates dismantling aggregates removal dysfunctional organelles. These are critical events prevent malfunction brain other parts line this idea, mutants linked onset progression neurodegeneration diseases. intricate molecular mechanisms that connect distinct pathologies continue be uncovered. Emerging evidence supports model controls cellular functions on multiple levels type specific fashion. Accordingly, derail homeostasis through several can instigate disease. Our review focuses association between neurodegeneration. We discuss latest insights field, emphasize open questions, speculate potential as drug target some most devastating forms

Language: Английский

Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology DOI
Carmine Settembre, Rushika M. Perera

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 223 - 245

Published: Nov. 24, 2023

Language: Английский

Citations

84
Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases DOI Creative Commons
Chih Hung Lo, Jialiu Zeng

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

Citations

52
The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy DOI Creative Commons
Elizabeth R. Gallagher, Erika L.F. Holzbaur

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

Citations

51
Brain drug delivery and neurodegenerative diseases: Polymeric PLGA-based nanoparticles as a forefront platform DOI
Miguel Pinto, Vera Silva, Sandra Barreiro

et al.

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 79, P. 101658 - 101658

Published: June 2, 2022

Language: Английский

Citations

51
Determinants, maintenance, and function of organellar pH DOI
Spencer A. Freeman, Sergio Grinstein, John Orlowski

et al.

Physiological Reviews, Journal Year: 2022, Volume and Issue: 103(1), P. 515 - 606

Published: Aug. 18, 2022

The protonation state of soluble and membrane-associated macromolecules dictates their charge, conformation, functional activity. In addition, protons (H + or equivalents) partake in numerous metabolic reactions serve as a source electrochemical energy to drive the transmembrane transport both organic inorganic substrates. Stringent regulation intracellular pH is therefore paramount homeostasis. Although cytosolic has been studied extensively, our understanding determinants H concentration ([H ]) organelles developed more slowly, limited by small size inaccessibility. Recently, however, targeting molecular probes organellar lumen together with advances genomic, proteomic, electrophysiological techniques have led identification characterization unique pumps, channels, transporters responsible for establishment maintenance intraorganellar pH. These developments implications cellular function health disease are subject this review.

Language: Английский

Citations

50
The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase DOI
Uche N. Medoh, Andy Hims, Julie Y. Chen

et al.

Science, Journal Year: 2023, Volume and Issue: 381(6663), P. 1182 - 1189

Published: Sept. 14, 2023

Lysosomes critically rely on bis(monoacylglycero)phosphate (BMP) to stimulate lipid catabolism, cholesterol homeostasis, and lysosomal function. Alterations in BMP levels monogenic complex neurodegeneration suggest an essential function human health. However, the site mechanism responsible for synthesis have been subject debate decades. Here, we report that Batten disease gene product CLN5 is elusive synthase (BMPS). BMPS-deficient cells exhibited a massive accumulation of precursor lysophosphatidylglycerol (LPG), depletion species, dysfunctional metabolism. Mechanistically, found BMPS mediated through energy-independent base exchange reaction between two LPG molecules with increased activity BMP-laden vesicles. Our study elucidates biosynthesis reveals anabolic late endosomes/lysosomes.

Language: Английский

Citations

33
The Niemann-Pick type diseases – A synopsis of inborn errors in sphingolipid and cholesterol metabolism DOI Creative Commons
Frank W. Pfrieger

Progress in Lipid Research, Journal Year: 2023, Volume and Issue: 90, P. 101225 - 101225

Published: March 31, 2023

Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation the underlying mechanisms and development efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) Niemann-Pick type C disease (NPCD) caused by specific variants sphingomyelin phosphodiesterase 1 (SMPD1) NPC intracellular cholesterol transporter (NPC1) or 2 (NPC2) genes that perturb key membrane components, cholesterol, respectively. Patients with severe forms these present visceral neurologic symptoms succumb premature death. This synopsis traces tortuous discovery diseases, highlights important advances respect genetic culprits cellular mechanisms, exposes efforts improve diagnosis explore new therapeutic approaches.

Language: Английский

Citations

28
A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice DOI Creative Commons
Franziska Richter, Miloš Stanojlović, Christopher Käufer

et al.

Neurotherapeutics, Journal Year: 2023, Volume and Issue: 20(1), P. 97 - 116

Published: Jan. 1, 2023

Development of neuroprotective therapeutics for Parkinson's disease (PD) is facing a lack translation from pre-clinical to clinical trials. One strategy improvement increase predictive validity studies by using extensively characterized animal models with comprehensive set validated pharmacodynamic readouts. Mice over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter (Thy1-aSyn line 61) reproduce key features sporadic PD, such as progressive loss striatal dopamine, pathology, deficits in motor and non-motor functions, elevation inflammatory markers. Extensive work this model multiple laboratories over past decade further increased confidence its robustness validity, especially analyzing pathomechanisms pathology down-stream pathways, drug testing. Interestingly, while postnatal transgene expression widespread central peripheral neurons, extent progression differs between brain regions, thereby replicating characteristic selective vulnerability neurodegenerative diseases. In-depth characterization these readouts conjunction behavioral has led more informative endpoints Each tested Thy1-aSyn 61 enhances knowledge on how molecular targets, functional are interconnected, optimizing platform towards Here, we present current state art target discovery, validation,

Language: Английский

Citations

22
Targeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct DOI Creative Commons
Alexandra Gehrlein, Vinod Udayar,

Nadia Anastasi

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 12, 2023

Abstract Mutations in glucocerebrosidase cause the lysosomal storage disorder Gaucher’s disease and are most common risk factor for Parkinson’s disease. Therapies to restore enzyme’s function brain hold great promise treating neurological implications. Thus, we developed blood-brain barrier penetrant therapeutic molecules by fusing transferrin receptor-binding moieties β-glucocerebrosidase (referred as GCase-BS). We demonstrate that these fusion proteins show significantly increased uptake efficiency compared enzyme alone. In a cellular model, GCase-BS rapidly rescues proteome lipid accumulations beyond known substrates. mouse intravenous injection of leads sustained reduction glucosylsphingosine can lower neurofilament-light chain plasma levels. Collectively, findings potential GBA1 -associated dysfunction, provide insight into candidate biomarkers, may ultimately open promising treatment paradigm diseases extending central nervous system.

Language: Английский

Citations

22
Gaucher disease provides a unique window into Parkinson disease pathogenesis DOI
Ellen Hertz, Yu Chen, Ellen Sidransky

et al.

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(9), P. 526 - 540

Published: Aug. 6, 2024

Language: Английский

Citations

11