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The increasing prevalence of Parkinson disease (PD) highlights the need to develop interventions aimed at slowing or halting its progression. As a result of sophisticated disease modeling in preclinical studies, and refinement of specific clinical/genetic/pathological profiles, our understanding of PD pathogenesis has grown over the years, leading to the identification of several targets for disease modification. This has translated to the development of targeted therapies, many of which have entered clinical trials. Nonetheless, up until now, none of these treatments have satisfactorily shown disease-modifying effects in PD. In this review, we present the most up-to-date disease-modifying pharmacological interventions in the clinical trial pipeline for PD. We focus on agents that have reached more advanced stages of clinical trials testing, highlighting both positive and negative results, and critically reflect on strengths, weaknesses, and challenges of current disease-modifying therapeutic avenues in PD.
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BACKGROUND: There is mounting evidence to suggest that high adherence to the Mediterranean diet (MedDiet) may reduce the risk of age-related diseases, including Parkinson's disease (PD). However, evidence for the role of the MedDiet in the relief of motor and non-motor symptoms in patients with PD remains limited and inconclusive. We provide a systematic review of the effects of the MedDiet on the clinical features of PD using data from randomised controlled trials (RCT) and prospective observational studies. METHODS: We searched MEDLINE, EMCare, EMBASE, Scopus and PubMed from inception until June 2023. Reference lists and the grey literature were also searched. Human studies with no restriction on language or publication date, examining associations between MedDiet adherence and the symptoms of PD, were included. We employed standard methodological procedures for data extraction and evidence synthesis and used the Quality Criteria Checklist for assessing the studies included. RESULTS: Four studies from three unique cohorts, including two observational studies (n = 1213) and one RCT (n = 70), met the inclusion criteria. Despite the short study duration reported in all included reports, high MedDiet adherence was associated with changes in the gut microbiota (e.g., increased abundance of short-chain fatty acids producers). These outcomes correlated with a significant improvement in several non-motor symptoms including cognitive dysfunction, dyspepsia and constipation. However, there were no significant changes in diarrhoea, gastrointestinal reflux, abdominal pain and motor symptoms. CONCLUSION: High MedDiet adherence may be associated with significant improvement in global cognition and several gastrointestinal symptoms, possibly associated to changes in gut microbiota composition. Further studies are warranted to clarify potential cause-and-effect relationships and to elucidate MedDiet impact on motor symptoms.
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Dieta Mediterránea , Microbioma Gastrointestinal , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/dietoterapia , Cooperación del Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto , Femenino , Masculino , Estudios Observacionales como Asunto , AncianoRESUMEN
The concept of a 'microbiota-gut-brain axis' has recently emerged as an important player in the pathophysiology of Parkinson disease (PD), not least because of the reciprocal interaction between gut bacteria and medications. The gut microbiota can influence levodopa kinetics, and conversely, drugs administered for PD can influence gut microbiota composition. Through a two-step enzymatic pathway, gut microbes can decarboxylate levodopa to dopamine in the small intestine and then dehydroxylate it to m-tyramine, thus reducing availability. Inhibition of bacterial decarboxylation pathways could therefore represent a strategy to increase levodopa absorption. Other bacterial perturbations common in PD, such as small intestinal bacterial overgrowth and Helicobacter pylori infection, can also modulate levodopa metabolism, and eradication therapies may improve levodopa absorption. Interventions targeting the gut microbiota offer a novel opportunity to manage disabling motor complications and dopa-unresponsive symptoms. Mediterranean diet-induced changes in gut microbiota composition might improve a range of non-motor symptoms. Prebiotics can increase levels of short-chain fatty acid-producing bacteria and decrease pro-inflammatory species, with positive effects on clinical symptoms and levodopa kinetics. Different formulations of probiotics showed beneficial outcomes on constipation, with some of them improving dopamine levels; however, the most effective dosage and duration and long-term effects of these treatments remain unknown. Data from faecal microbiota transplantation studies are preliminary, but show encouraging trends towards improvement in both motor and non-motor outcomes.This article summarises the most up-to-date knowledge in pharmacomicrobiomics in PD, and discusses how the manipulation of gut microbiota represents a potential new therapeutic avenue for PD.
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Microbioma Gastrointestinal , Infecciones por Helicobacter , Helicobacter pylori , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Microbioma Gastrointestinal/fisiología , Levodopa/farmacología , DopaminaRESUMEN
BACKGROUND: Variants in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD). They are also risk factors for Parkinson's disease (PD), and modify the expression of the PD phenotype. The penetrance of GBA1 variants in PD is incomplete, and the ability to determine who among GBA1 variant carriers are at higher risk of developing PD, would represent an advantage for prognostic and trial design purposes. OBJECTIVES: To compare the motor and non-motor phenotype of GBA1 carriers and non-carriers. METHODS: We present the cross-sectional results of the baseline assessment from the RAPSODI study, an online assessment tool for PD patients and GBA1 variant carriers. The assessment includes clinically validated questionnaires, a tap-test, the University of Pennsyllvania Smell Identification Test and cognitive tests. Additional, homogeneous data from the PREDICT-PD cohort were included. RESULTS: A total of 379 participants completed all parts of the RAPSODI assessment (89 GBA1-negative controls, 169 GBA1-negative PD, 47 GBA1-positive PD, 47 non-affected GBA1 carriers, 27 GD). Eighty-six participants were recruited through PREDICT-PD (43 non-affected GBA1 carriers and 43 GBA1-negative controls). GBA1-positive PD patients showed worse performance in visual cognitive tasks and olfaction compared to GBA1-negative PD patients. No differences were detected between non-affected GBA1 carriers carriers and GBA1-negative controls. No phenotypic differences were observed between any of the non-PD groups. CONCLUSIONS: Our results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, we did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers.
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Enfermedad de Gaucher , Enfermedad de Parkinson , Humanos , Estudios Transversales , Enfermedad de Parkinson/genética , Fenotipo , Penetrancia , Enfermedad de Gaucher/genética , Síntomas ProdrómicosRESUMEN
Caudo-rostral migration of pathological forms of α-synuclein from the gut to the brain is proposed as an early feature in Parkinson's disease pathogenesis, but the underlying mechanisms remain unknown. Intestinal epithelial enteroendocrine cells sense and respond to numerous luminal signals, including bacterial factors, and transmit this information to the brain via the enteric nervous system and vagus nerve. There is evidence that gut bacteria composition and their metabolites change in Parkinson's disease patients, and these alterations can trigger α-synuclein pathology in animal models of the disorder. Here, we investigated the effect of toll-like receptor and free fatty acid receptor agonists on the intracellular level of α-synuclein and its release using mouse secretin tumour cell line 1 enteroendocrine cells. Secretin tumour cell line 1 enteroendocrine cells were treated for 24 or 48â h with toll-like receptor agonists (toll-like receptor 4 selective lipopolysaccharide; toll-like receptor 2 selective Pam3CysSerLys4) and the free fatty acid receptor 2/3 agonists butyrate, propionate and acetate. The effect of selective receptor antagonists on the agonists' effects after 24â hours was also investigated. The level of α-synuclein protein was measured in cell lysates and cell culture media by western blot and enzyme-linked immunosorbent assay. The level of α-synuclein and tumour necrosis factor messenger RNA was measured by quantitative reverse transcription real-time polymerase chain reaction. Stimulation of secretin tumour cell line 1 enteroendocrine cells for 24 and 48â hours with toll-like receptor and free fatty acid receptor agonists significantly increased the amount of intracellular α-synuclein and the release of α-synuclein from the cells into the culture medium. Both effects were significantly reduced by antagonists selective for each receptor. Toll-like receptor and free fatty acid receptor agonists also significantly increased tumour necrosis factor transcription, and this was effectively inhibited by corresponding antagonists. Elevated intracellular α-synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce α-synuclein accumulation in secretin tumour cell line 1 enteroendocrine cells. Here, we provide support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in Parkinson's disease gut dysbiosis might facilitate accumulation of α-synuclein pathology in the gut.
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Compound 5 was identified from a high-throughput screening campaign as a small molecule pharmacological chaperone of glucocerebrocidase (GCase), a lysosomal hydrolase encoded by the GBA1 gene, variants of which are associated with Gaucher disease and Parkinson's disease. Further investigations revealed that compound 5 was slowly transformed into a regio-isomeric compound (6) in PBS buffer, plausibly via a ring-opening at hemiaminal moiety accompanied by subsequent intramolecular CC bond formation. Utilising this unexpected skeletal rearrangement reaction, a series of compound 6 analogues was synthesized which yielded multiple potent GCase pharmacological chaperones with sub-micromolar EC50 values as exemplified by compound 38 (EC50 = 0.14 µM).
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Enfermedad de Gaucher , Enfermedad de Parkinson , Humanos , Glucosilceramidasa/genética , Mutación , Enfermedad de Gaucher/tratamiento farmacológico , Chaperonas MolecularesRESUMEN
Recent attention has highlighted the importance of oral microbiota in human health and disease, e.g., in Parkinson's disease, notably using shotgun metagenomics. One key aspect for efficient shotgun metagenomic analysis relies on optimal microbial sampling and DNA extraction, generally implementing commercial solutions developed to improve sample collection and preservation, and provide high DNA quality and quantity for downstream analysis. As metagenomic studies are today performed on a large number of samples, the next evolution to increase study throughput is with DNA extraction automation. In this study, we proposed a semi-automated DNA extraction protocol for human salivary samples collected with a commercial kit, and compared the outcomes with the DNA extraction recommended by the manufacturer. While similar DNA yields were observed between the protocols, our semi-automated DNA protocol generated significantly higher DNA fragment sizes. Moreover, we showed that the oral microbiome composition was equivalent between DNA extraction methods, even at the species level. This study demonstrates that our semi-automated protocol is suitable for shotgun metagenomic analysis, while allowing for improved sample treatment logistics with reduced technical variability and without compromising the structure of the oral microbiome.
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ADN , Microbiota , Humanos , Análisis de Secuencia de ADN/métodos , ARN Ribosómico 16S/genética , ADN/genética , ADN/química , Microbiota/genética , MetagenomaRESUMEN
BACKGROUND AND OBJECTIVES: Cadaveric studies have shown disease-related neurodegeneration and other morphological abnormalities in the retina of individuals with Parkinson disease (PD); however, it remains unclear whether this can be reliably detected with in vivo imaging. We investigated inner retinal anatomy, measured using optical coherence tomography (OCT), in prevalent PD and subsequently assessed the association of these markers with the development of PD using a prospective research cohort. METHODS: This cross-sectional analysis used data from 2 studies. For the detection of retinal markers in prevalent PD, we used data from AlzEye, a retrospective cohort of 154,830 patients aged 40 years and older attending secondary care ophthalmic hospitals in London, United Kingdom, between 2008 and 2018. For the evaluation of retinal markers in incident PD, we used data from UK Biobank, a prospective population-based cohort where 67,311 volunteers aged 40-69 years were recruited between 2006 and 2010 and underwent retinal imaging. Macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layer (INL) thicknesses were extracted from fovea-centered OCT. Linear mixed-effects models were fitted to examine the association between prevalent PD and retinal thicknesses. Hazard ratios for the association between time to PD diagnosis and retinal thicknesses were estimated using frailty models. RESULTS: Within the AlzEye cohort, there were 700 individuals with prevalent PD and 105,770 controls (mean age 65.5 ± 13.5 years, 51.7% female). Individuals with prevalent PD had thinner GCIPL (-2.12 µm, 95% CI -3.17 to -1.07, p = 8.2 × 10-5) and INL (-0.99 µm, 95% CI -1.52 to -0.47, p = 2.1 × 10-4). The UK Biobank included 50,405 participants (mean age 56.1 ± 8.2 years, 54.7% female), of whom 53 developed PD at a mean of 2,653 ± 851 days. Thinner GCIPL (hazard ratio [HR] 0.62 per SD increase, 95% CI 0.46-0.84, p = 0.002) and thinner INL (HR 0.70, 95% CI 0.51-0.96, p = 0.026) were also associated with incident PD. DISCUSSION: Individuals with PD have reduced thickness of the INL and GCIPL of the retina. Involvement of these layers several years before clinical presentation highlight a potential role for retinal imaging for at-risk stratification of PD.
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Enfermedad de Parkinson , Células Ganglionares de la Retina , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Masculino , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/epidemiología , Tomografía de Coherencia Óptica/métodos , Estudios Retrospectivos , Estudios Prospectivos , Estudios Transversales , Fibras Nerviosas , Retina/diagnóstico por imagenRESUMEN
BACKGROUND: Variants in the GBA1 gene, which encodes lysosomal acid glucocerebrosidase, are among the most common genetic risk factors for Parkinson's disease and are associated with faster disease progression. The mechanisms involved are unresolved but might include accumulation of glucosylceramide. Venglustat is a brain-penetrant glucosylceramide synthase inhibitor that, in previous studies, reduced amounts of the glycosphingolipid. We aimed to assess the safety, efficacy, and target engagement of venglustat in people with early-stage Parkinson's disease carrying pathogenic GBA1 variants. METHODS: MOVES-PD part 2 was a randomised, double-blinded, placebo-controlled phase 2 study done at 52 centres (academic sites, specialty clinics, and general neurology centres) in 16 countries. Eligible adults aged 18-80 years with Parkinson's disease (Hoehn and Yahr stage ≤2) and one or more GBA1 variants were randomly assigned using an interactive voice-response system (1:1) to 52 weeks of treatment with oral venglustat (15 mg/day) or matching placebo. Investigators, site personnel, participants, and their caregivers were masked to treatment allocation. The primary outcome measure was the change from baseline to 52 weeks in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III combined score (a higher score indicates greater impairment), and it was analysed in a modified intention-to-treat population (ie, all randomly assigned participants with a baseline and at least one post-baseline measurement during the treatment period). This study was registered with ClinicalTrials.gov (NCT02906020) and is closed to recruitment. FINDINGS: Between Dec 15, 2016, and May 27, 2021, 221 participants were randomly assigned to venglustat (n=110) or placebo (n=111). The least squares mean change in MDS-UPDRS parts II and III combined score was 7·29 (SE 1·36) for venglustat (n=96) and 4·71 (SE 1·27) for placebo (n=105); the absolute difference between groups was 2·58 (95% CI -1·10 to 6·27; p=0·17). The most common treatment-emergent adverse events (TEAEs) were constipation and nausea (both were reported by 23 [21%] of 110 participants in the venglustat group and eight [7%] of 111 participants in the placebo group). Serious TEAEs were reported for 12 (11%) participants in each group. There was one death in the venglustat group owing to an unrelated cardiopulmonary arrest and there were no deaths in the placebo group. INTERPRETATION: In people with GBA1-associated Parkinson's disease in our study, venglustat had a satisfactory safety profile but showed no beneficial treatment effect compared with placebo. These findings indicate that glucosylceramide synthase inhibition with venglustat might not be a viable therapeutic approach for GBA1-associated Parkinson's disease. FUNDING: Sanofi.
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Enfermedad de Parkinson , Adulto , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Resultado del Tratamiento , Método Doble CiegoRESUMEN
The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. Biallelic variants in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder characterised by loss of GCase activity and aberrant intracellular accumulation of GCase substrates. Carriers of GBA1 variants have an increased risk of developing Parkinson disease (PD), with odds ratio ranging from 2.2 to 30 according to variant severity. GBA1 variants which do not cause GD in homozygosis can also increase PD risk. Patients with PD carrying GBA1 variants show a more rapidly progressive phenotype compared to non-carriers, emphasising the need for disease modifying treatments targeting the GBA1 pathway. Several mechanisms secondary to GCase dysfunction are potentially responsible for the pathological changes leading to PD. Misfolded GCase proteins induce endoplasmic reticulum stress and subsequent unfolded protein response and impair the autophagy-lysosomal pathway. This results in α-synuclein accumulation and spread, and promotes neurodegenerative changes. Preclinical evidence also shows that products of GCase activity can promote accumulation of α-synuclein, however there is no convincing evidence of substrate accumulation in GBA1-PD brains. Altered lipid homeostasis secondary to loss of GCase activity could also contribute to PD pathology. Treatments that target the GBA1 pathway could reverse these pathological processes and halt/slow the progression of PD. These range from augmentation of GCase activity via GBA1 gene therapy, restoration of normal intracellular GCase trafficking via molecular chaperones, and substrate reduction therapy. This review discusses the pathways associated with GBA1-PD and related novel GBA1-targeted interventions for PD treatment.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/uso terapéutico , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Glucosilceramidasa/uso terapéutico , Encéfalo/metabolismo , MutaciónRESUMEN
Mutations in GBA1, the gene encoding the lysosomal enzyme ß-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.
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Glucosilceramidasa , Enfermedad de Parkinson , Humanos , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Proteómica , Enfermedad de Parkinson/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Metabolismo Energético/genética , Mutación , Lisosomas/metabolismo , alfa-Sinucleína/metabolismo , Proteínas Mitocondriales/metabolismo , Proteasas ATP-Dependientes/metabolismoRESUMEN
PURPOSE OF REVIEW: Genetic variants in GBA1 and LRRK2 genes are the commonest genetic risk factor for Parkinson disease (PD); however, the preclinical profile of GBA1 and LRRK2 variant carriers who will develop PD is unclear. This review aims to highlight the more sensitive markers that can stratify PD risk in non-manifesting GBA1 and LRRK2 variant carriers. RECENT FINDINGS: Several case-control and a few longitudinal studies evaluated clinical, biochemical, and neuroimaging markers within cohorts of non-manifesting carriers of GBA1 and LRRK2 variants. Despite similar levels of penetrance of PD in GBA1 and LRRK2 variant carriers (10-30%), these individuals have distinct preclinical profiles. GBA1 variant carriers at higher risk of PD can present with prodromal symptoms suggestive of PD (hyposmia), display increased α-synuclein levels in peripheral blood mononuclear cells, and show dopamine transporter abnormalities. LRRK2 variant carriers at higher risk of PD might show subtle motor abnormalities, but no prodromal symptoms, higher exposure to some environmental factors (non-steroid anti-inflammatory drugs), and peripheral inflammatory profile. This information will help clinicians tailor appropriate screening tests and counseling and facilitate researchers in the development of predictive markers, disease-modifying treatments, and selection of healthy individuals who might benefit from preventive interventions.
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Enfermedad de Parkinson , Humanos , Glucosilceramidasa/genética , Heterocigoto , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Leucocitos Mononucleares , Estudios Longitudinales , Mutación , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Síntomas ProdrómicosRESUMEN
BACKGROUND: Biallelic pathogenic variants in GBA1 are the cause of Gaucher disease (GD) type 1 (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. Heterozygous GBA1 variants are also a common genetic risk factor for Parkinson's disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk for PD. OBJECTIVE: The objective of this study was to investigate the contribution of PD risk variants to risk for PD in patients with GD1. METHODS: We studied 225 patients with GD1, including 199 without PD and 26 with PD. All cases were genotyped, and the genetic data were imputed using common pipelines. RESULTS: On average, patients with GD1 with PD have a significantly higher PD genetic risk score than those without PD (P = 0.021). CONCLUSIONS: Our results indicate that variants included in the PD genetic risk score were more frequent in patients with GD1 who developed PD, suggesting that common risk variants may affect underlying biological pathways. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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Enfermedad de Gaucher , Enfermedad de Parkinson , Trastornos Parkinsonianos , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/genética , Trastornos Parkinsonianos/genética , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Factores de Riesgo , MutaciónRESUMEN
Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how the combined deficiencies of both enzymes might interact to modulate PD has yet to be explored. Therefore, we created a double-knockout (DKO) zebrafish line for both gba1 (or gba) and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO line compared to those for single mutants. Unexpectedly, DKO zebrafish maintained conventional swimming behaviour and had normalised neuronal gene expression signatures compared to those of single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKO zebrafish. Despite having an unexpected rescue effect, our results confirm ASM as a modifier of GBA1 deficiency in vivo. Our study highlights the need for validating how genetic variants and enzymatic deficiencies may interact in vivo.
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Enfermedad de Niemann-Pick Tipo A , Enfermedad de Parkinson , Animales , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Enfermedad de Parkinson/metabolismo , Fenotipo , alfa-Sinucleína/metabolismo , Mutación/genéticaRESUMEN
Microglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we video-recorded with time-lapse microscopy the changes in shape and motility occurring in primary cells derived from mice of both sexes in response to pro-inflammatory or neurotoxic stimulations. With this morpho-functional analysis, we documented distinct microglia subpopulations eliciting sex-specific responses to stimulation: male microglia tended to have a more pro-inflammatory phenotype, while female microglia showed increased sensitivity to conduritol-B-epoxide (CBE), a small molecule inhibitor of glucocerebrosidase, the enzyme encoded by the GBA1 gene, mutations of which are the major risk factor for Parkinson's Disease (PD). Interestingly, glucocerebrosidase inhibition particularly impaired the ability of female microglia to enhance the Nrf2-dependent detoxification pathway in neurons, attenuating the sex differences observed in this neuroprotective function. This finding is consistent with the clinical impact of GBA1 mutations, in which the 1.5-2-fold reduced risk of developing idiopathic PD observed in female individuals is lost in the GBA1 carrier population, thus suggesting a sex-specific role for microglia in the etiopathogenesis of PD-GBA1.
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Enfermedad de Parkinson , Animales , Femenino , Masculino , Ratones , Glucosilceramidasa/metabolismo , Microglía/metabolismo , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismoRESUMEN
Parkinson's disease (PD) is a common movement disorder, estimated to affect 4% of individuals by the age of 80. Mutations in the glucocerebrosidase 1 (GBA1) gene represent the most common genetic risk factor for PD, with at least 7-10% of non-Ashkenazi PD individuals carrying a GBA1 mutation (PD-GBA1). Although similar to idiopathic PD, the clinical presentation of PD-GBA1 includes a slightly younger age of onset, a higher incidence of neuropsychiatric symptoms, and a tendency to earlier, more prevalent and more significant cognitive impairment. The pathophysiological mechanisms underlying PD-GBA1 are incompletely understood, but, as in idiopathic PD, α-synuclein accumulation is thought to play a key role. It has been hypothesized that this overexpression of α-synuclein is caused by epigenetic modifications. In this paper, we analyze DNA methylation levels at 17 CpG sites located within intron 1 and the promoter of the α-synuclein (SNCA) gene in three different brain regions (frontal cortex, putamen and substantia nigra) in idiopathic PD, PD-GBA1 and elderly non-PD controls. In all three brain regions we find a tendency towards a decrease in DNA methylation within an eight CpG region of intron 1 in both idiopathic PD and PD-GBA1. The trend towards a reduction in DNA methylation was more pronounced in PD-GBA1, with a significant decrease in the frontal cortex. This suggests that PD-GBA1 and idiopathic PD have distinct epigenetic profiles, and highlights the importance of separating idiopathic PD and PD-GBA1 cases. This work also provides initial evidence that different genetic subtypes might exist within PD, each characterized by its own pathological mechanism. This may have important implications for how PD is diagnosed and treated.
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Glucosilceramidasa , Enfermedad de Parkinson , Humanos , Anciano , Glucosilceramidasa/metabolismo , alfa-Sinucleína/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/tratamiento farmacológico , Metilación de ADN , Intrones/genética , Mutación , Lóbulo Frontal/metabolismoRESUMEN
Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene, loss of function variants of which cause an autosomal recessive lysosomal storage disorder, Gaucher disease (GD). Heterozygous variants of GBA1 are also known as the strongest common genetic risk factor for Parkinson's disease (PD). Restoration of GCase enzymatic function using a pharmacological chaperone strategy is considered a promising therapeutic approach for PD and GD. We identified compound 4 as a GCase pharmacological chaperone with sub-micromolar activity from a high-throughput screening (HTS) campaign. Compound 4 was further optimised to ER-001230194 (compound 25). ER-001230194 shows improved ADME and physicochemical properties and therefore represents a novel pharmacological chaperone with which to investigate GCase pharmacology further.
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Enfermedad de Gaucher , Enfermedad de Parkinson , Humanos , Glucosilceramidasa/genética , Mutación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Gaucher/tratamiento farmacológico , LisosomasRESUMEN
Sequence variants or mutations in the GBA gene are numerically the most important risk factor for Parkinson disease (PD). The GBA gene encodes for the lysosomal hydrolase enzyme, glucocerebrosidase (GCase). GBA mutations often reduce GCase activity and lead to the impairment of the autophagy-lysosomal pathway, which is important in the turnover of alpha-synuclein, accumulation of which is a key pathological hallmark of PD. Although the E326K variant is one of the most common GBA variants associated with PD, there is limited understanding of its biochemical effects. We have characterized homozygous and heterozygous E326K variants in human fibroblasts. We found that E326K variants did not cause a significant loss of GCase protein or activity, endoplasmic reticulum (ER) retention or ER stress, in contrast to the L444P GBA mutation. This was confirmed in human dopaminergic SH-SY5Y neuroblastoma cell lines overexpressing GCase with either E326K or L444P protein. Despite no loss of the GCase activity, a significant increase in insoluble alpha-synuclein aggregates in E326K and L444P mutants was observed. Notably, SH-SY5Y overexpressing E326K demonstrated a significant increase in the lipid droplet number under basal conditions, which was exacerbated following treatment with the fatty acid oleic acid. Similarly, a significant increase in lipid droplet formation following lipid loading was observed in heterozygous and homozygous E326K fibroblasts. In conclusion, the work presented here demonstrates that the E326K mutation behaves differently to the common loss of function GBA mutations; however, lipid dyshomeostasis and alpha-synuclein pathology are still evident.
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Neuroblastoma , Enfermedad de Parkinson , Humanos , alfa-Sinucleína/genética , Gotas Lipídicas/metabolismo , Enfermedad de Parkinson/genética , Glucosilceramidasa/genética , Línea Celular , Lípidos , MutaciónRESUMEN
This review will focus on how bile acids are being used in clinical trials to treat neurological diseases due to their central involvement with the gut-liver-brain axis and their physiological and pathophysiological roles in both normal brain function and multiple neurological diseases. The synthesis of primary and secondary bile acids species and how the regulation of the bile acid pool may differ between the gut and brain is discussed. The expression of several bile acid receptors in brain and their currently known functions along with the tools available to manipulate them pharmacologically are examined, together with discussion of the interaction of bile acids with the gut microbiome and their lesser-known effects upon brain glucose and lipid metabolism. How dysregulation of the gut microbiome, aging and sex differences may lead to disruption of bile acid signalling and possible causal roles in a number of neurological disorders are also considered. Finally, we discuss how pharmacological treatments targeting bile acid receptors are currently being tested in an array of clinical trials for several different neurodegenerative diseases.