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

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 16, 2024

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

Language: Английский

---

Specialized astrocytes mediate glutamatergic gliotransmission in the CNS

Nature, Journal Year: 2023, Volume and Issue: 622(7981), P. 120 - 129

Published: Sept. 6, 2023

Abstract Multimodal astrocyte–neuron communications govern brain circuitry assembly and function 1 . For example, through rapid glutamate release, astrocytes can control excitability, plasticity synchronous activity 2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions 4–7 communicate fast focal they should possess an apparatus for Ca 2+ -dependent exocytosis similar neurons 8–10 However, the existence this mechanism has been questioned 11–13 owing inconsistent data 14–17 a lack direct supporting evidence. Here we revisited astrocyte hypothesis by considering emerging molecular heterogeneity 18–21 using molecular, bioinformatic imaging approaches, together with cell-specific genetic tools that interfere vivo. By analysing existing single-cell RNA-sequencing databases our patch-seq data, identified nine molecularly distinct clusters hippocampal astrocytes, among which found notable subpopulation selectively expressed synaptic-like glutamate-release machinery localized discrete sites. Using GluSnFR-based 22 situ vivo, corresponding subgroup responds reliably astrocyte-selective stimulations subsecond release events at spatially precise hotspots, were suppressed astrocyte-targeted deletion vesicular transporter (VGLUT1). Furthermore, or its isoform VGLUT2 revealed specific contributions glutamatergic cortico-hippocampal nigrostriatal circuits during normal behaviour pathological processes. uncovering atypical specialized adult brain, provide insights into complex roles central nervous system (CNS) physiology diseases, identify potential therapeutic target.

Language: Английский

---

Neuromelanin in Parkinson’s Disease: Tyrosine Hydroxylase and Tyrosinase

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(8), P. 4176 - 4176

Published: April 10, 2022

Parkinson’s disease (PD) is an aging-related and the second most common neurodegenerative after Alzheimer’s disease. The main symptoms of PD are movement disorders accompanied with deficiency neurotransmitter dopamine (DA) in striatum due to cell death nigrostriatal DA neurons. Two histopathological hallmarks exist PD: cytosolic inclusion bodies termed Lewy that mainly consist α-synuclein protein, oligomers which produced by misfolding regarded be neurotoxic, causing death; black pigments neuromelanin (NM) contained neurons markedly decrease PD. synthesis human NM similar melanin melanocytes; skin via DOPAquinone (DQ) tyrosinase, whereas DAquinone (DAQ) tyrosine hydroxylase (TH) aromatic L-amino acid decarboxylase (AADC). cytoplasm highly reactive assumed oxidized spontaneously or unidentified tyrosinase DAQ then, synthesized NM. Intracellular accumulation above a specific threshold has been reported associated neuron phenotypes. This review reports recent progress biosynthesis pathophysiology

Language: Английский

---

The brain-first vs. body-first model of Parkinson’s disease with comparison to alternative models

Journal of Neural Transmission, Journal Year: 2023, Volume and Issue: 130(6), P. 737 - 753

Published: April 16, 2023

Language: Английский

---

Gut microbiota produces biofilm-associated amyloids with potential for neurodegeneration

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 16, 2024

Abstract Age-related neurodegenerative diseases involving amyloid aggregation remain one of the biggest challenges modern medicine. Alterations in gastrointestinal microbiome play an active role aetiology neurological disorders. Here, we dissect amyloidogenic properties biofilm-associated proteins (BAPs) gut microbiota and their implications for synucleinopathies. We demonstrate that BAPs are naturally assembled as amyloid-like fibrils insoluble fractions isolated from human microbiota. show BAP genes part accessory genomes, revealing variability. Remarkably, abundance certain is correlated with Parkinson’s disease (PD) incidence. Using cultured dopaminergic neurons Caenorhabditis elegans models, report BAP-derived amyloids induce α-synuclein aggregation. Our results chaperone-mediated autophagy compromised by amyloids. Indeed, inoculation into brains wild-type mice promote key pathological features PD. Therefore, our findings establish use potential targets biomarkers α-synucleinopathies.

Language: Английский

---

Role of GABA pathway in motor and non-motor symptoms in Parkinson's disease: a bidirectional circuit

European journal of medical research, Journal Year: 2024, Volume and Issue: 29(1)

Published: March 27, 2024

Abstract Parkinson's disease (PD) is a progressive neurodegenerative as result of the degeneration dopaminergic neurons in substantia nigra pars compacta (SNpc). The fundamental features PD are motor and non-motor symptoms. symptoms develop due to disruption neurotransmitters other such γ-aminobutyric acid (GABA). potential role GABA neuropathology concerning was not precisely discussed. Therefore, this review intended illustrate possible regarding pathway essential regulating inhibitory tone prevent excessive stimulation cerebral cortex. Degeneration linked with reducing GABAergic neurotransmission. Decreasing activity promotes mitochondrial dysfunction oxidative stress, which highly related neuropathology. Hence, restoring by agonists may attenuate progression dysregulation SNpc contributes developing Besides, also pathway, amelioration reduce In conclusion, deregulation might be intricate Improving novel, beneficial approach control

Language: Английский

---

Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease

Science, Journal Year: 2025, Volume and Issue: 387(6736), P. 892 - 900

Published: Feb. 20, 2025

Neuronal accumulation and spread of pathological α-synuclein (α-syn) fibrils are key events in Parkinson's disease (PD) pathophysiology. However, the neuronal mechanisms underlying uptake α-syn remain unclear. In this work, we identified FAM171A2 as a PD risk gene that affects aggregation. Overexpressing promotes fibril endocytosis exacerbates neurotoxicity pathology. Neuronal-specific knockdown expression shows protective effects. Mechanistically, extracellular domain 1 interacts with C terminus through electrostatic forces, >1000 times more selective for fibrils. Furthermore, bemcentinib an effective blocker FAM171A2–α-syn interaction vitro binding assay, cellular models, mice. Our findings potential receptor and, thus, therapeutic target against PD.

Language: Английский

---

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

Biomedicines, Journal Year: 2022, Volume and Issue: 10(5), P. 1206 - 1206

Published: May 23, 2022

Astrocytes are essential for normal brain development and functioning. They respond to injury disease through a process referred as reactive astrogliosis, where the reactivity is highly heterogenous context-dependent. Reactive astrocytes active contributors pathology can exert beneficial, detrimental, or mixed effects following insults. Transforming growth factor-β (TGF-β) has been identified one of key factors regulating astrocyte reactivity. The genetic pharmacological manipulation TGF-β signaling pathway in animal models central nervous system (CNS) alters pathological functional outcomes. This review aims provide recent understanding regarding injury, aging, neurodegeneration. Further, it explores how modulates function context CNS injury.

Language: Английский

---

Striatal Blood–Brain Barrier Opening in Parkinson's Disease Dementia: A Pilot Exploratory Study

Movement Disorders, Journal Year: 2022, Volume and Issue: 37(10), P. 2057 - 2065

Published: June 28, 2022

Abstract Background Parkinson's disease (PD) exhibits a high prevalence of dementia as severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood–brain barrier (BBB) opening cortical regions in neurodegenerative disorders. The striatum is primary target delivery putative therapeutic agents PD. Objective Here, we report prospective, single‐arm, nonrandomized, proof‐of‐concept, phase I clinical trial (NCT03608553 amended) PD with to test the safety feasibility striatal BBB patients. Methods Seven patients cognitive impairment were treated posterior putamen. This was performed two sessions separated by 2 4 weeks, where second session included bilateral putamina 3 Primary outcome measures focal opening. Changes motor functions, magnetic resonance imaging (MRI), 18 F‐fluorodopa (FDOPA), β‐amyloid PET (positron emission tomography) images determined. Results procedure feasible well tolerated, no serious adverse events. No neurologically relevant change (battery neuropsychological tests) functions recognized at follow‐up. MRI revealed putamen closing shortly after treatment (24 hours 14 days) ruled out hemorrhagic ischemic lesions. There discrete but significant reduction uptake targeted region FDOPA PET. Conclusions These initial results indicate that FUS‐mediated safe therefore could become an effective tool facilitate neurorestorative molecules © 2022 International Parkinson Movement Disorder Society.

Language: Английский

---

BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

Science Advances, Journal Year: 2023, Volume and Issue: 9(16)

Published: April 19, 2023

Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal of adeno-associated virus serotype 9 vectors into brain regions involved Parkinson’s disease using low-intensity focus ultrasound adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically confirmed opening. Similar openings safely demonstrated three patients disease. In these one monkey, followed by 18 F-Choline uptake the putamen midbrain based on positron emission tomography. This indicates cellular binding molecules that otherwise would not enter parenchyma. The less-invasive nature this methodology could facilitate viral for gene therapy might allow early repeated interventions to treat neurodegenerative disorders.

Language: Английский

---