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

npj Parkinson s Disease, Год журнала: 2025, Номер 11(1)

Опубликована: Май 3, 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- to 6-month-old knock-in (VKI) mice. Spontaneous and optogenetically-evoked corticostriatal glutamate transmission increased VKI spiny projection neurons by 6 months unaffected acute leucine-rich repeat kinase 2 (LRRK2) inhibition. Total release iGluSnFR imaging similar wild-type. dLight revealed robust increases dopamine months, which were reversed with LRRK2 We conclude mice progressively emerges young-adulthood, dysfunction likely result sustained, rapidly-reversible, hyperactivity.

Язык: Английский

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Sex-specific perturbations of neuronal development caused by mutations in the autism risk gene DDX3X

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

Опубликована: Ноя. 22, 2024

ABSTRACT DDX3X is an X-linked RNA helicases that escapes X chromosome inactivation and expressed at higher levels in female brains. Mutations are associated with intellectual disability (ID) autism spectrum disorder (ASD) predominantly identified females. Using cellular mouse models, we show Ddx3x mediates sexual dimorphisms brain development a molecular, cellular, behavioral level. During cortical neuronal development, sustains female-biased signature of enhanced ribosomal biogenesis mRNA translation. Female neurons display proteins larger nucleoli, these sex obliterated by loss. regulates dendritic outgrowth sex- dose-dependent manner both male neurons, spine only neurons. Further, ablating conditionally forebrain sufficient to yield sex-specific changes developmental outcomes motor function. Together, findings pose as mediator differentiation during neurodevelopment open new avenues understand differences health disease.

Язык: Английский

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Mouse models for inherited monoamine neurotransmitter disorders

Journal of Inherited Metabolic Disease, Год журнала: 2024, Номер 47(3), С. 533 - 550

Опубликована: Янв. 2, 2024

Several mouse models have been developed to study human defects of primary and secondary inherited monoamine neurotransmitter disorders (iMND). As the field continues expand, current in corresponding include enzymes a molecular co-chaperone involved synthesis metabolism (PAH, TH, PITX3, AADC, DBH, MAOA, DNAJC6), tetrahydrobiopterin (BH

Язык: Английский

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

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

Опубликована: Фев. 24, 2024

ABSTRACT The impairment of dopaminergic (DA) neurons plays a central role in the development Parkinson’s disease. Evidence for distinct populations synaptic vesicles (SVs) differing neurotransmitter content (glutamate versus dopamine) has been attributed to differences trafficking pathways and their exocytosis kinetics. However, molecular ultrastructural organization two types remains poorly understood. Here we examined axonal varicosities human iPSC-derived DA glutamatergic (i 3 Neurons). While i Neurons are comprised 40-50 nm small clear SVs, predominantly large pleiomorphic including empty dense core vesicles, addition classical SVs. were positive VMAT2, monoamine vesicular transporter responsible loading dopamine, distinctly larger size spatially segregated from VGLUT1/2-positive when expressed an ectopic SV-like organelle reconstitution system. Moreover, these VMAT2-positive also colocalized known SV markers such as Rab3, SCAMP5, VAMP2, SV2C can be clustered by matrix protein synapsin. Our results show that display inherent neurotransmitter-containing secretory powerful models study presynaptic structures.

Язык: Английский

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Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3929 - 3929

Опубликована: Апрель 1, 2024

In the last two decades, alpha-synuclein (alpha-syn) assumed a prominent role as major component and seeding structure of Lewy bodies (LBs). This concept is driving ongoing research on pathophysiology Parkinson’s disease (PD). line with this, alpha-syn considered to be guilty protein in process, it may targeted through precision medicine modify progression. Therefore, designing specific tools block aggregation spreading represents effort development disease-modifying therapies PD. The present article analyzes concrete evidence about significance within LBs. this effort, some dogmas are challenged. concerns question whether more abundant compared other proteins Again, occurrence non-protein constituents scrutinized. Finally, LBs causing PD questioned. These revisited concepts helpful process validating which proteins, organelles, pathways likely involved damage meso-striatal dopamine neurons brain regions

Язык: Английский

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Pain in monogenic Parkinson’s disease: a comprehensive review

Frontiers in Neurology, Год журнала: 2023, Номер 14

Опубликована: Окт. 30, 2023

Pain, a challenging symptom experienced by individuals diagnosed with Parkinson’s disease (PD), still lacks comprehensive understanding of its underlying pathophysiological mechanisms. A systematic investigation prevalence and impact on the quality life in patients affected monogenic forms PD has yet to be undertaken. This review aims provide an overview association between pain PD, specifically focusing pathogenic variants SNCA , PRKN PINK1 PARK7 LRRK2 GBA1, VPS35, ATP13A2, DNAJC6, FBXO7 SYNJ1 . Sixty-three articles discussing associated were identified analyzed. The included studies exhibited significant heterogeneity design, sample size, outcome measures. Nonetheless, findings this suggest that may experience specific types depending variant present, distinguishing them from non-carriers. For instance, have reported painful dystonia, lower extremity pain, dorsal upper back pain. However, these observations are primarily based case reports unclear prevalence. Painful limb dystonia prominent symptoms carriers. continual correlation been noted mutations emergence though conflicting research outcomes pose challenges reaching definitive conclusions. Individuals mutation carriers also frequently report experiencing Pain as initial most troublesome one GBA1 -PD compared those idiopathic PD. evidence regarding PARK7, FBXO7, is limited insufficient. potential linkage genetic profiles holds promising clinical implications, allowing for stratification trials development personalized treatments In conclusion, underscores need further unravel intricate relationship Standardized methodologies, larger sizes, longitudinal essential elucidate mechanisms develop targeted therapeutic interventions management

Язык: Английский

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Selective dopaminergic vulnerability in Parkinson’s disease: new insights into the role of DAT

Frontiers in Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Авг. 24, 2023

One of the hallmarks Parkinson’s disease (PD) is progressive loss dopaminergic neurons and associated dopamine depletion. Several mechanisms, previously considered in isolation, have been proposed to contribute pathophysiology degeneration: oxidation-mediated neurotoxicity, high transporter (DAT) expression density per neuron, autophagy-lysosome pathway (ALP) dysfunction. However, interrelationships among these mechanisms remained unclear. Our recent research bridges this gap, recognizing autophagy as a novel homeostasis regulator, unifying concepts. I propose that modulates reuptake by selectively degrading DAT. In PD, ALP dysfunction could increase DAT enhance reuptake, oxidation, potentially contributing neurons. This integrated understanding may provide more comprehensive view aspects PD opens new avenues for therapeutic interventions.

Язык: Английский

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New insights in non-motor symptoms in Parkinson’s disease

Frontiers research topics, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

it is a pioneering approach to the world of academia, radically improving way scholarly research managed.The grand vision Frontiers where all people have an equal opportunity seek, share and generate knowledge.Frontiers provides immediate permanent online open access its publications, but this alone not enough realize our goals. journal seriesThe series multi-tier interdisciplinary set openaccess, journals, promising paradigm shift from current review, selection dissemination processes in academic publishing.All journals are driven by researchers for researchers; therefore, they constitute service community.At same time, operates on revolutionary invention, tiered publishing system, initially addressing specific communities scholars, gradually climbing up broader public understanding, thus serving interests lay society, too. Dedication qualityEach article landmark highest quality, thanks genuinely collaborative interactions between authors review editors, who include some world's best academicians.Research must be certified peers before entering stream knowledge that may eventually reach -and shape society; only applies most rigorous unbiased reviews.Frontiers revolutionizes freely delivering outstanding research, evaluated with no bias both social point view.By applying advanced information technologies, catapulting into new generation.

Язык: Английский

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Targeting selective autophagy in CNS disorders by small-molecule compounds

Pharmacology & Therapeutics, Год журнала: 2024, Номер 263, С. 108729 - 108729

Опубликована: Окт. 12, 2024

Язык: Английский

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Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson’s disease and Dementia with Lewy bodies

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Дек. 27, 2024

GBA is the major risk gene for Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB), two common α-synucleinopathies cognitive deficits. We investigated role of mutant in decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), Gba-SNCA double mice. Notably, mice showed early deficits but lacked PD-like motor or α-synuclein pathology. Conversely, tg displayed age-related deficits, without abnormalities. exhibited both exacerbated accompanied greater cortical phospho-α-synuclein pathology, especially layer 5 neurons. Single-nucleus RNA sequencing cortex uncovered synaptic vesicle (SV) endocytosis defects excitatory neurons mice, via robust downregulation genes regulating SV cycle synapse assembly. Immunohistochemistry electron microscopy validated these findings. Our results indicate that mutations, while exacerbating pre-existing aggregation contribute to through α-synuclein-independent mechanisms, involving dysfunction endocytosis.

Язык: Английский

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