Neurexin1 level in Huntington’s Disease and decreased Neurexin1 in disease progression DOI Creative Commons
Kyoungjoo Cho, Gyung Whan Kim

Neuroscience Research, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Huntington's disease (HD) is a neurodegenerative disorder characterized by the presence of abnormally expanded polyglutamine tracts in huntingtin protein (HTT). Mutant HTT disrupts synaptic transmission and plasticity, particularly striatum cortex, leading to early dysfunctions, such as altered neurotransmitter release, impaired vesicle recycling, disrupted postsynaptic receptor function. Synaptic loss precedes neuronal degeneration contributes progression. Neurexin1 (NRXN1), cell adhesion molecule primarily located presynaptic membrane, plays crucial role maintaining integrity. The present study investigated NRXN1 HD. This researched whether changed level has been related polyQ stretch Here, we report reduction levels post-symptomatic HD mice cells expressing tracts. was found decrease while increasing LAMP2A levels, which promotes lysosomal degradation NRXN1. In Q111, downregulated restored maintained proliferation compared with Q7. These findings suggest that regulated LAMP2A-mediated way decreased are associated symptomatic progression

Язык: Английский

A Pilot Proteomic Analysis of Huntington’s Disease by Functional Capacity DOI Creative Commons

Andrew McGarry,

Ruin Moaddel

Brain Sciences, Год журнала: 2025, Номер 15(1), С. 76 - 76

Опубликована: Янв. 16, 2025

Background: The molecular biology of Huntington's Disease (HD) has grown substantially, with pathological considerations extending to genetic modifiers, epigenetic changes, transcriptomics, the proteome, and metabolome. metabolome proteome are especially intriguing in that they most directly reflect functional state cellular environment, which may involve some combination pathology as well compensation. Methods: We assessed CSF proteomics from eight participants by their severity (TFC range 3-13), 47 proteins having a minimum r-value 0.7 nominal p-values < 0.05. Results: Our exploratory data reveal correlations between progression several processes including inflammation, ECM homeostasis NAD+ metabolism. Conclusions: Consistently identified targets correlate phenotype or have value, if validated, enrichment tools clinical trials potentially markers therapeutic response.

Язык: Английский

Процитировано

1
mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance DOI Open Access
Philip Stavrides, Chris N. Goulbourne,

James Peddy

и другие.

Опубликована: Янв. 28, 2025

Huntington’s disease (HD) is caused by expansion of the polyglutamine stretch in huntingtin protein (HTT) resulting hallmark aggresomes/inclusion bodies (IBs) composed mutant (mHTT) and its fragments. Stimulating autophagy to enhance mHTT clearance considered a potential therapeutic strategy for HD. Our recent evaluation autophagic-lysosomal pathway (ALP) human HD brain reveals upregulated lysosomal biogenesis relatively normal flux early Vonsattel grade brains, but impaired autolysosome late suggesting that stimulation could have benefits as an earlier clinical intervention. Here, we tested this hypothesis crossing Q175 knock-in model with our reporter mouse TRGL ( T hy-1- R FP- G L C3) investigate vivo neuronal ALP dynamics. In and/or TRGL/Q175 mice, was detected autophagic vacuoles also exhibited high level colocalization receptors p62/SQSTM1 ubiquitin IBs. Compared robust pathology late-stage striatum, alterations models are late-onset milder included lowered phospho-p70S6K level, lysosome depletion elevation including more poorly acidified autolysosomes larger-sized lipofuscin granules, reflecting flux. Administration mTOR inhibitor 6-mo-old normalized number, ameliorated aggresome while reducing mHTT-, p62- ubiquitin-immunoreactivities, beneficial modulation at stages progression.

Язык: Английский

Процитировано

1
Autophagy–lysosomal-associated neuronal death in neurodegenerative disease DOI
Ralph A. Nixon

Acta Neuropathologica, Год журнала: 2024, Номер 148(1)

Опубликована: Сен. 11, 2024

Язык: Английский

Процитировано

7
mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance DOI Open Access
Philip Stavrides, Chris N. Goulbourne,

James Peddy

и другие.

Опубликована: Янв. 28, 2025

Huntington’s disease (HD) is caused by expansion of the polyglutamine stretch in huntingtin protein (HTT) resulting hallmark aggresomes/inclusion bodies (IBs) composed mutant (mHTT) and its fragments. Stimulating autophagy to enhance mHTT clearance considered a potential therapeutic strategy for HD. Our recent evaluation autophagic-lysosomal pathway (ALP) human HD brain reveals upregulated lysosomal biogenesis relatively normal flux early Vonsattel grade brains, but impaired autolysosome late suggesting that stimulation could have benefits as an earlier clinical intervention. Here, we tested this hypothesis crossing Q175 knock-in model with our reporter mouse TRGL ( T hy-1- R FP- G L C3) investigate vivo neuronal ALP dynamics. In and/or TRGL/Q175 mice, was detected autophagic vacuoles also exhibited high level colocalization receptors p62/SQSTM1 ubiquitin IBs. Compared robust pathology late-stage striatum, alterations models are late-onset milder included lowered phospho-p70S6K level, lysosome depletion elevation including more poorly acidified autolysosomes larger-sized lipofuscin granules, reflecting flux. Administration mTOR inhibitor 6-mo-old normalized number, ameliorated aggresome while reducing mHTT-, p62- ubiquitin-immunoreactivities, beneficial modulation at stages progression.

Язык: Английский

Процитировано

0
mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance DOI Open Access
Philip Stavrides, Chris N. Goulbourne,

James Peddy

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 30, 2024

Huntington's disease (HD) is caused by expansion of the polyglutamine stretch in huntingtin protein (HTT) resulting hallmark aggresomes/inclusion bodies (IBs) composed mutant (mHTT) and its fragments. Stimulating autophagy to enhance mHTT clearance considered a potential therapeutic strategy for HD. Our recent evaluation autophagic-lysosomal pathway (ALP) human HD brain reveals upregulated lysosomal biogenesis relatively normal flux early Vonsattel grade brains, but impaired autolysosome late suggesting that stimulation could have benefits as an earlier clinical intervention. Here, we tested this hypothesis crossing Q175 knock-in model with our reporter mouse TRGL (

Язык: Английский

Процитировано

2
Methamphetamine Increases Tubulo-Vesicular Areas While Dissipating Proteins from Vesicles Involved in Cell Clearance DOI Open Access
Gloria Lazzeri, Paola Lenzi, Carla L. Busceti

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(17), С. 9601 - 9601

Опубликована: Сен. 4, 2024

Cytopathology induced by methamphetamine (METH) is reminiscent of degenerative disorders such as Parkinson’s disease, and it characterized membrane organelles arranged in tubulo-vesicular structures. These areas, appearing clusters vesicles, have never been defined concerning the presence specific organelles. Therefore, present study aimed to identify relative absolute area membrane-bound following a moderate dose (100 µM) METH administered catecholamine-containing PC12 cells. Organelles antigens were detected immunofluorescence, they further quantified plain electron microscopy situ stoichiometry. This analysis indicated an increase autophagosomes damaged mitochondria along with decrease lysosomes healthy mitochondria. Following METH, severe dissipation hallmark proteins from their own vesicles was measured. In fact, amounts LC3 p62 reduced within autophagy vacuoles compared whole cytosol. Similarly, LAMP1 Cathepsin-D reduced. findings suggest loss compartmentalization confirm competence cell clearing during catecholamine degeneration. Such entropy consistent energy stores, which routinely govern appropriate subcellular compartmentalization.

Язык: Английский

Процитировано

0
Neurexin1 level in Huntington’s Disease and decreased Neurexin1 in disease progression DOI Creative Commons
Kyoungjoo Cho, Gyung Whan Kim

Neuroscience Research, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Huntington's disease (HD) is a neurodegenerative disorder characterized by the presence of abnormally expanded polyglutamine tracts in huntingtin protein (HTT). Mutant HTT disrupts synaptic transmission and plasticity, particularly striatum cortex, leading to early dysfunctions, such as altered neurotransmitter release, impaired vesicle recycling, disrupted postsynaptic receptor function. Synaptic loss precedes neuronal degeneration contributes progression. Neurexin1 (NRXN1), cell adhesion molecule primarily located presynaptic membrane, plays crucial role maintaining integrity. The present study investigated NRXN1 HD. This researched whether changed level has been related polyQ stretch Here, we report reduction levels post-symptomatic HD mice cells expressing tracts. was found decrease while increasing LAMP2A levels, which promotes lysosomal degradation NRXN1. In Q111, downregulated restored maintained proliferation compared with Q7. These findings suggest that regulated LAMP2A-mediated way decreased are associated symptomatic progression

Язык: Английский

Процитировано

0