Dataset Information

Early deficits in an in vitro striatal microcircuit model carrying the Parkinson's GBA-N370S mutation.

ABSTRACT: Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson's disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chambered microfluidic platform and established a cortico-striato-nigral microcircuit partially recapitulating the striatal presynaptic landscape in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, cortical glutamatergic projections facilitated MSN synaptic activity, and dopaminergic transmission enhanced maturation of MSNs in vitro. Replacement of wild-type iPSC-derived dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-related GBA-N370S mutation led to a depolarisation of resting membrane potential and an increase in rheobase in iPSC-MSNs, as well as a reduction in both voltage-gated sodium and potassium currents. Such deficits were resolved in late microcircuit cultures, and could be reversed in younger cultures with antagonism of protein kinase A activity in iPSC-MSNs. Taken together, our results highlight the unique utility of modelling striatal neurons in a modular physiological circuit to reveal mechanistic insights into GBA1 mutations in PD.

SUBMITTER: Do QB

PROVIDER: S-EPMC11014935 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Early deficits in an in vitro striatal microcircuit model carrying the Parkinson's GBA-N370S mutation.

Do Quyen B QB Noor Humaira H Marquez-Gomez Ricardo R Cramb Kaitlyn M L KML Ng Bryan B Abbey Ajantha A Ibarra-Aizpurua Naroa N Caiazza Maria Claudia MC Sharifi Parnaz P Lang Charmaine C Beccano-Kelly Dayne D Baleriola Jimena J Bengoa-Vergniory Nora N Wade-Martins Richard R

NPJ Parkinson's disease 20240412 1

Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson's disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chambered microfluidic platform and established a cortico-striato-nigral microcircuit partially recapitulating the striatal presynaptic landscape in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, cortical glutamatergic projections facilitated MSN synaptic activit ...[more]

PMID: 38609392

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Project description:Individuals with mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing Parkinson's disease with cognitive deficit. We examined whether visual short-term memory impairments, long associated with patients with Parkinson's disease, are also present in GBA-positive individuals-both with and without Parkinson's disease. Precision of visual working memory was measured using a serial order task in which participants observed four bars, each of a different colour and orientation, presented sequentially at screen centre. Afterwards, they were asked to adjust a coloured probe bar's orientation to match the orientation of the bar of the same colour in the sequence. An additional attentional 'filtering' condition tested patients' ability to selectively encode one of the four bars while ignoring the others. A sensorimotor task using the same stimuli controlled for perceptual and motor factors. There was a significant deficit in memory precision in GBA-positive individuals-with or without Parkinson's disease-as well as GBA-negative patients with Parkinson's disease, compared to healthy controls. Worst recall was observed in GBA-positive cases with Parkinson's disease. Although all groups were impaired in visual short-term memory, there was a double dissociation between sources of error associated with GBA mutation and Parkinson's disease. The deficit observed in GBA-positive individuals, regardless of whether they had Parkinson's disease, was explained by a systematic increase in interference from features of other items in memory: misbinding errors. In contrast, impairments in patients with Parkinson's disease, regardless of GBA status, was explained by increased random responses. Individuals who were GBA-positive and also had Parkinson's disease suffered from both types of error, demonstrating the worst performance. These findings provide evidence for dissociable signature deficits within the domain of visual short-term memory associated with GBA mutation and with Parkinson's disease. Identification of the specific pattern of cognitive impairment in GBA mutation versus Parkinson's disease is potentially important as it might help to identify individuals at risk of developing Parkinson's disease.

Project description:BackgroundGlucocerebrosidase (GBA) heterozygous variants are the most important genetic risk factor for the development of alpha-synucleinopathies (i.e., Parkinson's disease and Dementia with Lewy Bodies). Herein, we report for the first time on a patient with a clinical diagnosis of Posterior Cortical Atrophy, carrier of the common GBA heterozygous variant N370S (c.1226A > G).Case presentationA 44-year-old woman with positive familial history for Dementia with Lewy Bodies disclosed three related signs characterizing the Balint's syndrome: ocular apraxia, optic ataxia and simultanagnosia. Over 2-year follow up, overt gaze apraxia (psychic paralysis of gaze) appeared leading to functional blindness. Given her young age at onset and positive familial history, she underwent a next-generation-sequencing (NGS) based screening of a panel of 32 genes related to neurodegenerative conditions within the ANAMNESYS (An origiNal Approach to study faMiliarity in NEurodegenerative SYndromeS) study. NGS demonstrated the N370S variant in the GBA gene (rs76763715), confirmed by Sanger sequencing. This is a relatively common variant, with predicted mild impact, already reported to occur in 2.4% of PD Italian patients; however, neither this nor other GBA variants have ever been reported to date in patients with Posterior Cortical Atrophy. Glucocerebrosidase activity was investigated and found to be significantly reduced (4.72 nmol/h/mg) compared to healthy controls as well as patients affected by neurodegenerative diseases, further supporting pathogenicity of the GBA variant.ConclusionsWe report on a patient with a clinical diagnosis of Posterior Cortical Atrophy, carrier of the GBA heterozygous variant N370S (c.1226A > G; p.Asn409Ser) determining reduced GCase activity. This report also confirms the role of NGS-based targeted gene analysis in detecting peculiar clinical phenotypes associated with known pathogenic mutations and reinforces the knowledge that carriers of genetic variants often present phenotypic overlaps across different neurodegenerative syndromes, highlighting the limitations of current clinical diagnostic criteria in defining boundaries between distinct conditions and the difficulties of clinicians in reaching the best clinical diagnosis.

Dataset Information

Early deficits in an in vitro striatal microcircuit model carrying the Parkinson's GBA-N370S mutation.

Publications

Early deficits in an in vitro striatal microcircuit model carrying the Parkinson's GBA-N370S mutation.

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