Single nuclei RNA-seq reveals a medium spiny neuron glutamate excitotoxicity signature prior to the onset of neuronal death in an ovine Huntington’s disease model DOI Creative Commons
Andrew Jiang, Linya You, Renée R. Handley

et al.

Human Molecular Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: May 13, 2024

Abstract Huntington’s disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of huntingtin (HTT) gene resulting behavioural, cognitive, and motor defects. Current knowledge pathogenesis remains incomplete, no course-modifying interventions are clinical use. We have previously reported development characterisation OVT73 transgenic sheep model HD. The 73 polyglutamine somatically stable therefore likely captures prodromal phase with absence symptomatology even at 5-years age detectable striatal cell loss. To better understand disease-initiating events we undertaken single nuclei transcriptome study striatum extensively studied cohort 5-year-old HD matched wild-type controls. identified transcriptional upregulation genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) kainate receptors medium spiny neurons, type preferentially lost early Further, observed astrocytic glutamate uptake transporters neuron GABAA receptors, which may maintain homeostasis. Taken together, these observations support excitotoxicity hypothesis as neurodegeneration cascade-initiating process but threshold toxicity be regulated several protective mechanisms. Addressing this biochemical defect prevent neuronal loss avoid more complex secondary consequences precipitated death.

Language: Английский

The Formation and Function of the VTA Dopamine System DOI Open Access
Guoqiang Hou,

Hao Mei,

Jiawen Duan

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3875 - 3875

Published: March 30, 2024

The midbrain dopamine system is a sophisticated hub that integrates diverse inputs to control multiple physiological functions, including locomotion, motivation, cognition, reward, as well maternal and reproductive behaviors. Dopamine neurotransmitter binds G-protein-coupled receptors. also works together with other neurotransmitters various neuropeptides maintain the balance of synaptic functions. dysfunction leads several conditions, Parkinson’s disease, Huntington’s major depression, schizophrenia, drug addiction. ventral tegmental area (VTA) has been identified an important relay nucleus modulates homeostatic plasticity in system. Due complexity transmissions input–output connections VTA, structure function this crucial brain region are still not fully understood. In review article, we mainly focus on cell types, neurotransmitters, neuropeptides, ion channels, receptors, neural circuits VTA system, hope obtaining new insight into formation vital region.

Language: Английский

Citations

16
The impact of interleukin-6 (IL-6) and mesenchymal stem cell-derived IL-6 on neurological conditions DOI Creative Commons
Irina Kerkis, Álvaro Rossan de Brandão Prieto da Silva, Rodrigo Pinheiro Araldi

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: June 24, 2024

Interleukin-6 (IL-6) is a versatile cytokine crucial for immune response modulation, inflammation regulation, and various physiological processes in the body. Its wide-ranging functions underscore its importance maintaining health. Dysregulated IL-6 closely associated with many diseases, making it key research therapeutic target. Elevated levels central nervous system worsen neuroinflammation neurodegenerative diseases by activating microglia astrocytes releasing pro-inflammatory cytokines neurotoxic molecules. Moreover, dysregulated weakens blood-brain barrier, exacerbating neuronal damage allowing peripheral cells inflammatory mediators to enter brain. Mesenchymal stem (MSCs) show promise modulating regulating levels. They effectively suppress cytokines, including IL-6, while promoting anti-inflammatory factors. This approach highlights of targeting other alleviate adverse effects on neurological disorders. review provides comprehensive overview IL-6’s involvement disorders, examining endogenous derived from MSCs. We explore mechanisms affecting function, survival, modulation system. Additionally, we discuss potential MSC-derived neuroregeneration neuroprotection. By elucidating interplay pathologies, this offers insights into novel strategies signaling pathways

Language: Английский

Citations

13
Polyglutamine disorders: Pathogenesis and potential drug interventions DOI
Shweta Tandon, Prerna Aggarwal, Surajit Sarkar

et al.

Life Sciences, Journal Year: 2024, Volume and Issue: 344, P. 122562 - 122562

Published: March 14, 2024

Language: Английский

Citations

8
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

et al.

Published: Jan. 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.

Language: Английский

Citations

1
Computational Assessment of the Phytochemicals of Panax ginseng C.A. Meyer Against Dopamine Receptor D1 for Early Huntington’s Disease Prophylactics DOI
Jhashanath Adhikari Subin, Ram Lal Shrestha

Cell Biochemistry and Biophysics, Journal Year: 2024, Volume and Issue: 82(4), P. 3413 - 3423

Published: July 24, 2024

Language: Английский

Citations

6
Genetics and precision genomics approaches to pulmonary hypertension DOI Creative Commons
Eric D. Austin, Micheala A. Aldred, Mona Alotaibi

et al.

European Respiratory Journal, Journal Year: 2024, Volume and Issue: 64(4), P. 2401370 - 2401370

Published: Aug. 29, 2024

Considerable progress has been made in the genomics of pulmonary arterial hypertension (PAH) since 6th World Symposium on Pulmonary Hypertension, with identification rare variants several novel genes, as well common that confer a modest increase PAH risk. Gene and variant curation by an expert panel now provides robust framework for knowing which genes to test how interpret clinical practice. We recommend genetic testing be offered specific subgroups symptomatic patients PAH, children certain types group 3 (PH). Testing asymptomatic family members use genetics reproductive decision-making require involvement experts. Large cohorts biospecimens exist extension non-group 1 PH begun. However, these are largely European origin; greater diversity will essential characterise full extent genomic variation contributing risk treatment responses. Other omics data also being incorporated. Furthermore, advance gene- pathway-specific care targeted therapies, gene-specific registries support their families lay foundation genetically informed trials. This international outreach collaboration between patients/families, clinicians researchers. Ultimately, harmonisation patient-derived biospecimens, omic information, analytic approaches field.

Language: Английский

Citations

6
The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders DOI Open Access
Anna Stasiłowicz-Krzemień,

Wiktoria Nogalska,

Zofia Maszewska

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 5749 - 5749

Published: May 25, 2024

Neurological disorders present a wide range of symptoms and challenges in diagnosis treatment. Cannabis sativa, with its diverse chemical composition, offers potential therapeutic benefits due to anticonvulsive, analgesic, anti-inflammatory, neuroprotective properties. Beyond cannabinoids, cannabis contains terpenes polyphenols, which synergistically enhance pharmacological effects. Various administration routes, including vaporization, oral ingestion, sublingual, rectal, provide flexibility treatment delivery. This review shows the efficacy managing neurological such as epilepsy, neurodegenerative diseases, neurodevelopmental disorders, psychiatric painful pathologies. Drawing from surveys, patient studies, clinical trials, it highlights alleviating symptoms, slowing disease progression, improving overall quality life for patients. Understanding mechanisms can open up possibilities using this plant individual needs.

Language: Английский

Citations

5
Space exploration and risk of Parkinson’s disease: a perspective review DOI Creative Commons
Nilufar Ali, Afshin Beheshti,

Greg Hampikian

et al.

npj Microgravity, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 3, 2025

Systemic mitochondrial dysfunction, dopamine loss, sustained structural changes in the basal ganglia including reduced tyrosine hydroxylase, and altered gait- these effects observed space-flown animals astronauts mirrors Parkinson's disease (PD). Evidence of human cells, examined through lens PD, suggests that spaceflight-induced PD-like molecular are important to monitor during deep space exploration. These changes, may potentially elevate risk PD astronauts.

Language: Английский

Citations

0
One BAG doesn’t fit all: the differences and similarities of BAG family members in mediating CNS homeostasis DOI
Heng Lin,

S.V. Ramanan,

S.J. Kaplan

et al.

Biological Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

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

et al.

Published: Jan. 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.

Language: Английский

Citations

0