ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling

The Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 221(7)

Published: June 3, 2022

Mutations in VPS13C cause early-onset, autosomal recessive Parkinson’s disease (PD). We have established that encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In current study, we demonstrate depleting HeLa cells causes an accumulation of lysosomes with altered profile, including di-22:6-BMP, biomarker PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. addition, DNA-sensing cGAS-STING pathway, which was recently implicated PD pathogenesis, is activated these cells. This activation results from combination elevated mitochondrial DNA cytosol defect degradation STING, lysosome-dependent process. These suggest link ER-lysosome innate immune model human cell line place pathways relevant pathogenesis.

Language: Английский

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Cell biology of Parkinson's disease: Mechanisms of synaptic, lysosomal, and mitochondrial dysfunction

Current Opinion in Neurobiology, Journal Year: 2024, Volume and Issue: 85, P. 102841 - 102841

Published: Feb. 1, 2024

Language: Английский

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Pharmacological Mechanism of the Non-hallucinogenic 5-HT_2A Agonist Ariadne and Analogs

ACS Chemical Neuroscience, Journal Year: 2022, Volume and Issue: 14(1), P. 119 - 135

Published: Dec. 15, 2022

Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group α-position amine. has been tested humans including clinical trials at Bristol-Myers Company indicate lack hallucinogenic effects and remarkable therapeutic effects, such as rapid remission psychotic symptoms schizophrenics, relaxation catatonics, complete Parkinson's disease (PD), improved cognition geriatric subjects. Despite these provocative results, compound abandoned drug candidate its molecular pharmacology remained unknown. Here, we report detailed examination vitro vivo analogs, propose hypothesis for potential this class. We also provide summary previous preclinical results contextualize signaling data. Our show serotonin 5-HT2 receptor agonist, exhibits modest selectivity over 5-HT1 receptors, no relevant activity 5-HT4,5,7 other aminergic substantial affinity plasma membrane monoamine transporters. Compared DOM, shows lower potency efficacy multiple pathways examined (Gq, G11, β-arrestin2) coupled 5-HT2A receptors. confirmed shift α-propyl docking rationale progressive decrease with growing length α-substituent. versus DOM apparent change relative preference between Gq/11 activation β-arrestin2 recruitment; instead, there small but consistent drop channels. acts agonist mice markedly attenuated head twitch response (HTR) comparison studies rabbits, cats, dogs. Hence, explanatory model dramatically hallucinosis-like animals (5-HT2A hypothesis). In terms reverse translation noted used auxilin knockout where rescued severe motor deficits mouse line, on par l-DOPA, notable finding considering Ariadne's dopamine receptors emerges prototype new class, agonists, considerable across psychiatric neurological indications.

Language: Английский

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Recent updates on structural insights of MAO-B inhibitors: a review on target-based approach

Molecular Diversity, Journal Year: 2023, Volume and Issue: 28(3), P. 1823 - 1845

Published: March 28, 2023

Language: Английский

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Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties

Psychopharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

Abstract Recent research with classic psychedelics suggests significant therapeutic potential, particularly for neuropsychiatric disorders. A mediating influence behind symptom resolution is thought to be the personal insight – at times, bordering on mystical one acquires during acute phase of a psychedelic session. Indeed, current clinical trials have found strong correlations between subjective effects (ASE) under and their enduring properties. However, potential barriers widespread implementation, including healthcare resource-intensive nature sessions exclusion certain at-risk patient groups, there an active search determine whether ASE elimination can accompanied by retention persisting benefits these class compounds. Recognizing aberrant underlying neural circuitry that characterizes range disorders, promote neuroplastic changes may correct abnormal circuitry, investigators are rushing design discover compounds psychoplastogenic, but not hallucinogenic (i.e., ASE), potential. These efforts paved discovery ‘non-psychedelic/subjective psychedelics’, or lack activity efficacy in preclinical models. This review aims distill evidence both surrounding question: dissociated from sustained properties? Several plausible scenarios then proposed offer clarity potentially answer this question.

Language: Английский

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Synaptic vesicle characterization of iPSC-derived dopaminergic neurons provides insight into distinct secretory vesicle pools

npj Parkinson s Disease, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 9, 2025

Abstract The dysfunction of dopaminergic (DA) neurons is central to Parkinson’s disease. Distinct synaptic vesicle (SV) populations, differing in neurotransmitter content (dopamine vs. glutamate), may vary due differences trafficking and exocytosis. However, the structural organization these vesicles remains unclear. In this study, we examined axonal varicosities human iPSC-derived DA glutamatergic (i 3 Neurons). i Neurons primarily contained small, clear SVs (40–50 nm), whereas larger, pleiomorphic including dense core empty vesicles, addition classical SVs. VMAT2-positive neurons, which load dopamine, were spatially segregated from VGLUT1/2-positive an SV-like reconstitution system. These also colocalized with SV markers (e.g., VAMP2, SV2C), can be clustered by synapsin. Moreover, terminals mouse striata showed similar pool diversity. findings reveal neurons’ highlighting as effective models for studying presynaptic structures.

Language: Английский

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Dysfunction of synaptic endocytic trafficking in Parkinson’s disease

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 19(12), P. 2649 - 2660

Published: March 1, 2024

Parkinson’s disease is characterized by the selective degeneration of dopamine neurons in nigrostriatal pathway and deficiency striatum. The precise reasons behind specific these remain largely elusive. Genetic investigations have identified over 20 causative PARK genes 90 genomic risk loci associated with both familial sporadic disease. Notably, several are linked to synaptic vesicle recycling process, particularly clathrin-mediated endocytosis pathway. This suggests that impaired might represent an early feature disease, followed axonal eventual loss cell bodies midbrain via a “dying back” mechanism. Recently, new animal cellular models disease-linked mutations affecting endocytic been created extensively characterized. These faithfully recapitulate certain disease-like features at animal, circuit, levels, exhibit defects membrane trafficking, further supporting findings from human genetics clinical studies. In this review, we will first summarize molecular two clathrin uncoating proteins: auxilin ( DNAJC6 / PARK19 ) synaptojanin 1 SYNJ1 PARK20 ). mouse carrying gene phenocopy each other terminal pathology display potent synergistic effect. Subsequently, delve into involvement endocytosis-related proteins (GAK, endophilin A1, SAC2/INPP5F, synaptotagmin-11), as factors through genome-wide association studies, pathogenesis. We also explore direct or indirect roles some common (alpha-synuclein (PARK1/4), Parkin (PARK2), LRRK2 (PARK8)) trafficking. Additionally, discuss emerging novel functions downstream traffic pathways, autophagy. Given dysfunction considered event deeper understanding mechanisms underlying trafficking may unveil targets for diagnosis development interventional therapies Future research should aim elucidate why generalized leads

Language: Английский

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Diverse Functions of Parkin in Midbrain Dopaminergic Neurons

Movement Disorders, Journal Year: 2024, Volume and Issue: 39(8), P. 1282 - 1288

Published: June 10, 2024

Abstract Parkinson's disease (PD) is characterized by preferential degeneration of midbrain dopaminergic neurons that contributes to its typical clinical manifestation. Mutations in the parkin gene ( PARK2 ) represent a relatively common genetic cause early onset PD. Parkin has been implicated PINK1‐dependent mitochondrial quantity control targeting dysfunctional mitochondria lysosomes via mitophagy. Recent evidence suggests can be activated PINK1‐independent manner regulate synaptic function human neurons. Neuronal activity triggers CaMKII‐mediated activation and recruitment vesicles where promotes binding synaptojanin‐1 endophilin A1 facilitates vesicle endocytosis. In PD patient neurons, disruption this pathway on loss leads defective recycling accumulation toxic oxidized dopamine at least part explains vulnerability These findings suggest convergent mechanism for PD‐linked mutations parkin, synaptojanin‐1, highlight dysfunction as an pathogenic event © 2024 The Author(s). Movement Disorders published Wiley Periodicals LLC behalf International Parkinson Disorder Society.

Language: Английский

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Seeking rhythmic patterns in microglial cells within the circadian pineal gland from male rats

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Abstract Microglia, the innate immune cells of brain, constitute a highly dynamic cell population that displays several functions influenced by light:dark (L:D) cycle. Within pineal gland (PG), key organ circadian timing system, microglia actively participate in its development and homeostasis. However, little is known about their rhythmic features this organ. This study aimed to elucidate morphological functional phenotypes microglial at two time points L:D We performed immunofluorescence staining confocal microscopy on paraffin-embedded sections from 3– 18-month-old Wistar rats, analyzing samples collected midday (ZT6) midnight (ZT18). Our results showed density spatial distribution IBA1 + did not vary between ZT6 ZT18 3-month-old PG. these exhibited reduced size amoeboid-like shapes, along with reduction expression phagocytosis inhibitor SIRP alpha, compared ZT6. Moreover, were immunoreactive for lysosomal marker CD68 autophagic LC3B both ZTs. Additionally, contacts PAX6 detected ZTs analyzed. Interestingly, attenuated or abolished rhythmicity parameters alpha levels findings suggest undergo transitions into alerted states night, characterized small, rounded shapes enhanced phagocytic capacity. adaptation likely prepares them respond potential invading agents other insults PG, which could impact nocturnal melatonin production. Key Microglia within rat exhibit daily adaptations, enhancing effectivity against challenges time-dependent manner. Oscillatory diminish aging, suggesting an attenuation functions. Nocturnal reactivity may influence physiology, potentially affecting synthesis.

Language: Английский

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Emergent glutamate & dopamine dysfunction in VPS35(D620N) knock-in mice and rapid reversal by LRRK2 inhibition

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

The D620N variant in Vacuolar Protein Sorting 35 (VPS35) causes autosomal-dominant, late-onset Parkinson’s disease. VPS35 is a core subunit of the retromer complex that canonically recycles transmembrane cargo from sorting endosomes. Although cargoes include many synaptic proteins, VPS35’s neuronal functions are poorly understood. To investigate consequences mutation, striatal neurotransmission was assessed 1-, 3- & 6-month-old knock-in (VKI) mice. Spontaneous and optogenetically-evoked corticostriatal glutamate transmission increased VKI spiny projection neurons by 6 months, when total release, quantified iGluSnFR imaging, showed similarities to wild-type. dLight imaging revealed robust increases dopamine release which were reversed with acute ex vivo leucine-rich repeat kinase 2 (LRRK2) inhibition. We conclude mice progressively emerges young-adulthood, dysfunction likely result sustained, rapidly-reversible, LRRK2 hyperactivity.

Language: Английский

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