Molecular Imaging of the GABAergic System in Parkinson’s Disease and Atypical Parkinsonisms

Terkelsen, Miriam Højholt; Hvingelby, Victor Schwartz; Pavese, Nicola

doi:10.1007/s11910-022-01245-z

Cited by 11 publications

(4 citation statements)

References 44 publications

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“…These findings support the idea that loss of dopaminergic neurons is the primary pathology in PD, consistent with the SCENIC result (Fig. 2I), and add insight into the recent interest in the GABAergic pathway associated with hypokinesia and other accompanying symptoms of PD [69,140] The integration analysis of spatial transcriptomes of our data revealed two distinct major groups of neuronal clusters with distinct spatial distributions in the SN and VTA regions: NC6,11,1,3,7,8,9 and NC2,5,10 (Fig. 2F).…”

Section: Discussionsupporting

confidence: 89%

Single-nucleus and spatial transcriptomic analysis identified molecular features of neuronal heterogeneity and distinct glial responses in Parkinson’s disease

Yoo,

Lee,

Seo

et al. 2024

Preprint

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The heterogeneity of Parkinson's disease (PD) is increasingly recognized as an important aspect of understanding the disorder. Among the factors contributing to this heterogeneity, ethnic differences are primary sources, significantly influencing the likelihood of PD developing and its initial symptoms' nature. While there have been numerous reports related to PD in East Asia, there has been a lack of contribution from single-cell (or nucleus) transcriptome studies, which have been making significant contributions to understanding PD. In this study, a total of 33,293 nuclei obtained from the substantia nigra (SN) of confirmed pathological PD and control patients in South Korea were profiled, revealing eight different cell types through cluster analysis. Monocle-based pseudotime analysis identified two disease-associated trajectories for each astrocyte and microglia and identified genes that differentiate them. Interestingly, we uncovered the inflammatory intervention in the early PD-associated transition in microglia and identified the molecular features of this intermediate state of microglia. In addition, gene regulatory networks (GRNs) based on TENET analysis revealed the detrimental effect of an HSPA5-led module in microglia and MSRB3- and HDAC8- led modules specifying the two different astrocyte trajectories. In SN neurons, we observed population changes, a decrease in dopaminergic and glutamatergic neurons and a proportional increase in GABAergic neurons. By deconvolution in spatial transcriptome obtained the PD sample, we confirmed spatiotemporal heterogeneity of neuronal subpopulations and PD-associated progressive gliosis specific to dopaminergic nuclei, SN and ventral tegmental areas (VTAs). In conclusion, our approach has enabled us to identify the genetic and spatial characterization of neurons and to demonstrate different glial fates in PD. These findings advance our molecular understanding of cell type-specific changes in the progression of Korean PD, providing an important foundation for predicting and validating interventions or drug effects for future treatments.

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Section: Discussionsupporting

confidence: 89%

Single-nucleus and spatial transcriptomic analysis identified molecular features of neuronal heterogeneity and distinct glial responses in Parkinson’s disease

Yoo,

Lee,

Seo

et al. 2024

Preprint

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“…Growing evidence has reported alterations in the GABAergic system in PD, which are associated with motor symptoms, psychomotor symptoms, axial symptoms, cognitive impairment, olfactory dysfunction, and visual hallucinations. [508][509][510] An alteration in the synthesis and metabolism of GABA was recently reported in a metagenomic analysis of the PD gut microbiome. 331 Recent studies have explored the potential therapeutic role of probiotics and prebiotics in addressing these underlying pathologies.…”

Section: Serotoninmentioning

confidence: 99%

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

Loh,

Mak,

Tan

et al. 2024

Sig Transduct Target Ther

107

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The human gastrointestinal tract is populated with a diverse microbial community. The vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect of human biology, including health maintenance, development, aging, and disease. The advent of new sequencing technologies and culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations to shed light on microbiome–host interactions. Evidence has unveiled the bidirectional communication between the gut microbiome and the central nervous system, referred to as the “microbiota–gut–brain axis”. The microbiota–gut–brain axis represents an important regulator of glial functions, making it an actionable target to ameliorate the development and progression of neurodegenerative diseases. In this review, we discuss the mechanisms of the microbiota–gut–brain axis in neurodegenerative diseases. As the gut microbiome provides essential cues to microglia, astrocytes, and oligodendrocytes, we examine the communications between gut microbiota and these glial cells during healthy states and neurodegenerative diseases. Subsequently, we discuss the mechanisms of the microbiota–gut–brain axis in neurodegenerative diseases using a metabolite-centric approach, while also examining the role of gut microbiota-related neurotransmitters and gut hormones. Next, we examine the potential of targeting the intestinal barrier, blood–brain barrier, meninges, and peripheral immune system to counteract glial dysfunction in neurodegeneration. Finally, we conclude by assessing the pre-clinical and clinical evidence of probiotics, prebiotics, and fecal microbiota transplantation in neurodegenerative diseases. A thorough comprehension of the microbiota–gut–brain axis will foster the development of effective therapeutic interventions for the management of neurodegenerative diseases.

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“…For example, those to the striatum are mirrored by GABAergic projections behind the midbrain and SNpc. Altered dopaminergic activity in PD substantially impacts the GABAergic circuitry of the SNpc and impacts the excitation/inhibition balance in the cortex 91 . Numerous brainstem nuclei are engaged in fundamental homeostatic mechanisms, including gastrointestinal regulation, pain perception, mood control, and sleep‐wake cycles, 92 all of which are impacted by PD.…”

Section: Gaba Pathway and Pd Neuropathologymentioning

confidence: 99%

Sleep disorders cause Parkinson's disease or the reverse is true: Good GABA good night

Al‐kuraishy,

Al‐Gareeb,

Albuhadily

et al. 2024

CNS Neurosci Ther

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BackgroundParkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non‐motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ‐aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non‐motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD.AimSleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD‐related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non‐motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non‐motor symptoms.ConclusionThere is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation.

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Molecular Imaging of the GABAergic System in Parkinson’s Disease and Atypical Parkinsonisms

Cited by 11 publications

References 44 publications

Single-nucleus and spatial transcriptomic analysis identified molecular features of neuronal heterogeneity and distinct glial responses in Parkinson’s disease

Single-nucleus and spatial transcriptomic analysis identified molecular features of neuronal heterogeneity and distinct glial responses in Parkinson’s disease

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

Sleep disorders cause Parkinson's disease or the reverse is true: Good GABA good night

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