Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.

Direct activation of microglia by ß-glucosylceramide causes phagocytosis of neurons that exacerbates Gaucher disease.

Gaucher disease (GD) is the most common lysosomal storage disease caused by recessive mutations in the degrading enzyme of ß-glucosylceramide (ß-GlcCer). However, it remains unclear how ß-GlcCer causes severe neuronopathic symptoms, which are not fully treated by current therapies. We herein found that ß-GlcCer accumulating in GD activated microglia through macrophage-inducible C-type lectin (Mincle) to induce phagocytosis of living neurons, which exacerbated Gaucher symptoms. This process was augmented by tumor necrosis factor (TNF) secreted from activated microglia that sensitized neurons for phagocytosis. This characteristic pathology was also observed in human neuronopathic GD. Blockade of these pathways in mice with a combination of FDA-approved drugs, minocycline (microglia activation inhibitor) and etanercept (TNF blocker), effectively protected neurons and ameliorated neuronopathic symptoms. In this study, we propose that limiting unrestrained microglia activation using drug repurposing provides a quickly applicable therapeutic option for fatal neuronopathic GD.

Parkinson's Disease Genetics and Pathophysiology.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by degeneration of the substantia nigra pars compacta and by accumulation of α-synuclein in Lewy bodies. PD is caused by a combination of environmental factors and genetic variants. These variants range from highly penetrant Mendelian alleles to alleles that only modestly increase disease risk. Here, we review what is known about the genetics of PD. We also describe how PD genetics have solidified the role of endosomal, lysosomal, and mitochondrial dysfunction in PD pathophysiology. Finally, we highlight how all three pathways are affected by α-synuclein and how this knowledge may be harnessed for the development of disease-modifying therapeutics.

Comparison of different promoters to improve AAV vector-mediated gene therapy for neuronopathic Gaucher disease.

Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene. It can manifest with severe neurodegeneration and visceral pathology. The most acute neuronopathic form (nGD), for which there are no curative therapeutic options, is characterised by devastating neuropathology and death during infancy. In this study, we investigated the therapeutic benefit of systemically delivered AAV9 vectors expressing the human GBA1 gene at two different doses comparing a neuronal-selective promoter with ubiquitous promoters. Our results highlight the importance of a careful evaluation of the promoter sequence used in gene delivery vectors, suggesting a neuron-targeted therapy leading to high levels of enzymatic activity in the brain but lower GCase expression in the viscera, might be the optimal therapeutic strategy for nGD.

PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases.

Mutations in GBA1, encoding glucocerebrosidase (GCase), cause Gaucher disease (GD) and are also genetic risks in developing Parkinson's disease (PD). Currently, the approved therapies are only effective for directly treating visceral symptoms, but not for primary neuronopathic involvement in GD (nGD). Progranulin (PGRN), encoded by GRN, is a novel modifier of GCase, but the impact of PGRN in GBA1 mutation-associated pathologies in vivo remains unknown. Herein, Grn-/- mice crossed into Gba9v/9v mice, a Gba1 mutant line homozygous for the Gba1 D409V mutation, generating Grn-/-Gba9v/9v (PG9V) mice. PG9V mice exhibited neurobehavioral deficits, early onset, and more severe GD phenotypes compared to Grn-/- and Gba9v/9v mice. Moreover, PG9V mice also displayed PD-like phenotype. Mechanistic analysis revealed that PGRN deficiency caused severe neuroinflammation with microgliosis and astrogliosis, along with impaired autophagy associated with the Gba1 mutation. A PGRN-derived peptide, termed ND7, ameliorated the disease phenotype in GD patient fibroblasts ex vivo. Unexpectedly, ND7 penetrated the blood-brain barrier (BBB) and effectively ameliorated the nGD manifestations and PD pathology in Gba9v/null and PG9V mice. Collectively, this study not only provides the first line of in vivo but also ex vivo evidence demonstrating the crucial role of PGRN in GBA1/Gba1 mutation-related pathologies, as well as a clinically relevant mouse model for mechanistic and potential therapeutics studies for nGD and PD. Importantly, a BBB penetrant PGRN-derived biologic was developed that may provide treatment for rare lysosomal storage diseases and common neurodegenerative disorders, particularly nGD and PD.

Cholinergic innervation topography in GBA-associated de novo Parkinson's disease patients.

The most common genetic risk factors for Parkinson's disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand 18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD. The study investigated 123 newly diagnosed, treatment-naïve Parkinson's disease subjects-with confirmed presynaptic dopaminergic deficits on PET imaging. Whole-gene GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment of all cognitive domains, motor evaluation with the Unified Parkinson's Disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and 18F-FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non-GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume of interest-based approaches. The degree of overlap between t-maps from two-sample t-test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower 18F-FEOBV binding was found in both the GBA-PD and non-GBA-PD groups compared to controls. Dice (P < 0.05, cluster size 100) showed good overlap (0.7326) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in 18F-FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal and frontal cortices (P < 0.05, FDR-corrected). In volume of interest analyses (Bonferroni corrected), the left parahippocampal gyrus was more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding. Although the Parkinson's disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. A larger group is needed to validate these findings. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical phenotypic differences between carriers versus non-carrier groups are observable.

Gba1 E326K renders motor and non-motor symptoms with pathologic α-syn, tau and glial activation.

Mutations in the GBA1 gene are common genetic risk factors for Parkinson's disease (PD), disrupting enzymatic activity and causing lysosomal dysfunction, leading to elevated α-synuclein (α-syn) levels. While GBA1's role in synucleinopathy is well-established, recent research underscores neuroinflammation as a significant pathogenic mechanism in GBA1 deficiency. This study investigates neuroinflammation in Gba1 E326K knock-in mice, a model associated with increased PD and dementia risk. At 9 and 24 months, we assessed GBA1 protein and activity, α-synuclein pathology, neurodegeneration, motor deficits, and gliosis in the ventral midbrain and hippocampus using immunohistochemistry (IHC), Western blot (WB), and GCase assays. Additionally, primary microglia from WT and GBA1E326K/E326K mice were treated with α-syn preformed fibrils (PFF) to study microglia activation, pro-inflammatory cytokines, reactive astrocyte formation, and neuronal death through qPCR, WB, and immunocytochemistry analyses. We also evaluated the effects of gut inoculation of α-syn PFF in Gba1 E326K mice at 7 months and striatal inoculation at 10 months, assessing motor/non-motor symptoms, α-syn pathology, neuroinflammation, gliosis, and neurodegeneration via behavioural tests, IHC, and WB assays. At 24 months, Gba1 E326K knock-in mice showed reduced GCase enzymatic activity and glucosylceramide build-up in the ventral midbrain and hippocampus. Increased pro-inflammatory cytokines and reactive astrocytes were observed in microglia and astrocytes from Gba1 E326K mice treated with pathologic α-syn PFF. Gut inoculation of α-syn PFF increased Lewy body accumulation in the hippocampal dentate gyrus, with heightened microglia and astrocyte activation and worsened non-motor symptoms. Intrastriatal α-syn preformed fibril injection induced motor deficits, reactive glial protein accumulation, and tauopathy in the prefrontal cortex and hippocampus of Gba1 E326K mice. GBA1 deficiency due to the Gba1 E326K mutation exacerbates neuroinflammation and promotes pathogenic α-synuclein transmission, intensifying disease pathology in PD models. This study enhances our understanding of how the Gba1 E326K mutation contributes to neuroinflammation and the spread of pathogenic α-syn in the brain, suggesting new therapeutic strategies for PD and related synucleinopathies.

Variant-specific effects of GBA1 mutations on dopaminergic neuron proteostasis.

Glucocerebrosidase 1 (GBA1) mutations are the most important genetic risk factors for Parkinson's disease (PD). Clinically, mild (e.g., p.N370S) and severe (e.g., p.L444P and p.D409H) GBA1 mutations have different PD phenotypes, with differences in age at disease onset, progression, and the severity of motor and non-motor symptoms. We hypothesize that GBA1 mutations cause the accumulation of α-synuclein by affecting the cross-talk between cellular protein degradation mechanisms, leading to neurodegeneration. Accordingly, we tested whether mild and severe GBA1 mutations differentially affect the degradation of α-synuclein via the ubiquitin-proteasome system (UPS), chaperone-mediated autophagy (CMA), and macroautophagy and differentially cause accumulation and/or release of α-synuclein. Our results demonstrate that endoplasmic reticulum (ER) stress and total ubiquitination rates were significantly increased in cells with severe GBA1 mutations. CMA was found to be defective in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons with mild GBA1 mutations, but not in those with severe GBA1 mutations. When examining macroautophagy, we observed reduced formation of autophagosomes in cells with the N370S and D409H GBA1 mutations and impairments in autophagosome-lysosome fusion in cells with the L444P GBA1 mutation. Accordingly, severe GBA1 mutations were found to trigger the accumulation and release of oligomeric α-synuclein in iPSC-derived dopaminergic neurons, primarily as a result of increased ER stress and defective macroautophagy, while mild GBA1 mutations affected CMA, which is mainly responsible for the degradation of the monomeric form of α-synuclein. Overall, our findings provide new insight into the molecular basis of the clinical variability in PD associated with different GBA1 mutations.

Role of GBA variants in Lewy body disease neuropathology.

Rare and common GBA variants are risk factors for both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (ß: -0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0-1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease-risk associations of GBA in PD, PD dementia, and DLB.

Altered TFEB subcellular localization in nigral neurons of subjects with incidental, sporadic and GBA-related Lewy body diseases.

Transcription factor EB (TFEB) is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis of GBA-related and sporadic Parkinson's disease (PD), and dementia with Lewy bodies (DLB). TFEB activation results in its translocation from the cytosol to the nucleus. Here, we investigated TFEB subcellular localization and its relation to intracellular alpha-synuclein (aSyn) accumulation in post-mortem human brain of individuals with either incidental Lewy body disease (iLBD), GBA-related PD/DLB (GBA-PD/DLB) or sporadic PD/DLB (sPD/DLB), compared to control subjects. We analyzed nigral dopaminergic neurons using high-resolution confocal and stimulated emission depletion (STED) microscopy and semi-quantitatively scored the TFEB subcellular localization patterns. We observed reduced nuclear TFEB immunoreactivity in PD/DLB patients compared to controls, both in sporadic and GBA-related cases, as well as in iLBD cases. Nuclear depletion of TFEB was more pronounced in neurons with Ser129-phosphorylated (pSer129) aSyn accumulation in all groups. Importantly, we observed previously-unidentified TFEB-immunopositive perinuclear clusters in human dopaminergic neurons, which localized at the Golgi apparatus. These TFEB clusters were more frequently observed and more severe in iLBD, sPD/DLB and GBA-PD/DLB compared to controls, particularly in pSer129 aSyn-positive neurons, but also in neurons lacking detectable aSyn accumulation. In aSyn-negative cells, cytoplasmic TFEB clusters were more frequently observed in GBA-PD/DLB and iLBD patients, and correlated with reduced GBA enzymatic activity as well as increased Braak LB stage. Altered TFEB distribution was accompanied by a reduction in overall mRNA expression levels of selected TFEB-regulated genes, indicating a possible early dysfunction of lysosomal regulation. Overall, we observed cytoplasmic TFEB retention and accumulation at the Golgi in cells without apparent pSer129 aSyn accumulation in iLBD and PD/DLB patients. This suggests potential TFEB impairment at the early stages of cellular disease and underscores TFEB as a promising therapeutic target for synucleinopathies.

GPNMB Biomarker Levels in GBA1 Carriers with Lewy Body Disorders.

BACKGROUND: The GPNMB single-nucleotide polymorphism rs199347 and GBA1 variants both associate with Lewy body disorder (LBD) risk. GPNMB encodes glycoprotein nonmetastatic melanoma protein B (GPNMB), a biomarker for GBA1-associated Gaucher's disease. OBJECTIVE: The aim of this study was to determine whether GPNMB levels (1) differ in LBD with and without GBA1 variants and (2) associate with rs199347 genotype. METHODS: We quantified GPNMB levels in plasma and cerebrospinal fluid (CSF) from 124 individuals with LBD with one GBA1 variant (121 plasma, 14 CSF), 631 individuals with LBD without GBA1 variants (626 plasma, 41 CSF), 9 neurologically normal individuals with one GBA1 variant (plasma), and 2 individuals with two GBA1 variants (plasma). We tested for associations between GPNMB levels and rs199347 or GBA1 status. RESULTS: GPNMB levels associate with rs199347 genotype in plasma (P = 0.022) and CSF (P = 0.007), but not with GBA1 status. CONCLUSIONS: rs199347 is a protein quantitative trait locus for GPNMB. GPNMB levels are unaltered in individuals carrying one GBA1 variant. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Frequency of Hereditary and GBA1-Related Parkinsonism in Latin America: A Systematic Review and Meta-Analysis.

BACKGROUND: Identifying hereditary parkinsonism is valuable for diagnosis, genetic counseling, patient prioritization in trials, and studying the disease for personalized therapies. However, most studies were conducted in Europeans, and limited data exist on admixed populations like those from Latin America. OBJECTIVES: This study aims to assess the frequency and distribution of genetic parkinsonism in Latin America. METHODS: We conducted a systematic review and meta-analysis of the frequency of parkinsonian syndromes associated with genetic pathogenic variants in Latin America. We defined hereditary parkinsonism as those caused by the genes outlined by the MDS Nomenclature of Genetic Movement Disorders and heterozygous carriers of GBA1 pathogenic variants. A systematic search was conducted in PubMed, Web of Science, Embase, and LILACS in August 2022. Researchers reviewed titles and abstracts, and disagreements were resolved by a third researcher. After this screening, five researchers reanalyzed the selection criteria and extracted information based on the full paper. The frequency for each parkinsonism-related gene was determined by the presence of pathogenic/likely pathogenic variants among screened patients. Cochran's Q and I2 tests were used to quantify heterogeneity. Meta-regression, publication bias tests, and sensitivity analysis regarding study quality were also used for LRRK2-, PRKN-, and GBA1-related papers. RESULTS: We included 73 studies involving 3014 screened studies from 16 countries. Among 7668 Latin American patients, pathogenic variants were found in 19 different genes. The frequency of the pathogenic variants in LRRK2 was 1.38% (95% confidence interval [CI]: 0.52-2.57), PRKN was 1.16% (95% CI: 0.08-3.05), and GBA1 was 4.17% (95% CI: 2.57-6.08). For all meta-analysis, heterogeneity was high and publication bias tests were negative, except for PRKN, which was contradictory. Information on the number of pathogenic variants in the other genes is further presented in the text. CONCLUSIONS: This study provides insights into hereditary and GBA1-related parkinsonism in Latin America. Lower GBA1 frequencies compared to European/North American cohorts may result from limited access to gene sequencing. Further research is vital for regional prevalence understanding, enabling personalized care and therapies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

GBA1 rs3115534 Is Associated with REM Sleep Behavior Disorder in Parkinson's Disease in Nigerians.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) is an early feature of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Damaging coding variants in Glucocerebrosidase (GBA1) are a genetic risk factor for RBD. Recently, a population-specific non-coding risk variant (rs3115534) was found to be associated with PD risk and earlier onset in individuals of African ancestry. OBJECTIVES: We aimed to investigate whether the GBA1 rs3115534 PD risk variant is associated with RBD in persons with PD. METHODS: We studied 709 persons with PD and 776 neurologically healthy controls from Nigeria. All DNA samples were genotyped and imputed, and the GBA1 rs3115534 risk variant was extracted. The RBD screening questionnaire (RBDSQ) was used to assess symptoms of possible RBD. RESULTS: RBD was present in 200 PD (28.2%) and 51 (6.6%) controls. We identified that the non-coding GBA1 rs3115534 risk variant is associated with possible RBD in individuals of Nigerian origin (ß, 0.3640; standard error [SE], 0.103, P = 4.093e-04), as well as in all samples after adjusting for PD status (ß, 0.2542; SE, 0.108; P = 0.019) suggesting that although non-coding, this variant may have the same downstream consequences as GBA1 coding variants. CONCLUSIONS: Our results indicate that the non-coding GBA1 rs3115534 risk variant is associated with an increasing number of RBD symptoms in persons with PD of Nigerian origin. Further research is needed to assess if this variant is also associated with polysomnography-defined RBD and with RBD symptoms in DLB. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Phenotypic consequences of GBA1 pathological variant R463C (p.R502C).

Gaucher disease (GD) is an autosomal recessively inherited lysosomal storage disorder caused by biallelic pathological variants in the GBA1 gene. Patients present along a broad clinical spectrum, and phenotypes are often difficult to predict based on genotype alone. The variant R463C (p.Arg502Cys) exemplifies this challenge. To better characterize its different clinical presentations, we examined the records of 25 current and historical patients evaluated at the National Institutes of Health. Nine patients were classified as GD1, 14 were classified as GD3, and two had an ambiguous diagnosis between GD1 and GD3. In addition, we reviewed the published literature in PubMed and Web of Science through December 2023, identifying 62 cases with an R463C variant from 18 countries. Within the NIH cohort, the most common second variants were N370S (p.N409S) and L444P (p.L483P). R463C/L444P was encountered in patients with GD1 and GD3 in both the NIH cohort and worldwide. In the literature, R463C/R463C was also reported in both GD1 and GD3, although sparse phenotypic information was shared. Often the phenotype reflected what might be predicted for the second mutant allele. This diversity of phenotypes emphasizes the need for longitudinal follow-up to assess symptom development and neurological involvement.

Adult type I Gaucher disease with splenectomy caused by a compound heterozygous GBA1 mutation in a Chinese patient: a case report.

Gaucher disease (GD) is an autosomal recessive ailment resulting from glucocerebrosidase deficiency caused by a mutation in the GBA1 gene, leading to multi-organ problems in the liver, spleen, and bone marrow. In China, GD is extremely uncommon and has a lower incidence rate than worldwide. In this study, we report the case of an adult male with an enlarged spleen for 13 years who presented with abdominal distension, severe loss of appetite and weight, reduction of the three-line due to hypersplenism, frequent nosebleeds, and bloody stools. Regrettably, the unexpected discovery of splenic pathology suggestive of splenic Gaucher disease was only made after a splenectomy due to a lack of knowledge about rare disorders. Our patient's delayed diagnosis may have been due to the department where he was originally treated, but it highlights the need for multidisciplinary consultation in splenomegaly of unknown etiology. We then investigated the patient's clinical phenotypes and gene mutation features using genetically phenotypical analysis. The analysis of the GBA1 gene sequence indicated that the patient carried a compound heterozygous mutation consisting of two potentially disease-causing mutations: c.907C > A (p. Leu303Ile) and c.1448 T > C (p. Leu483Pro). While previous research has linked the p. Leu483Pro mutation site to neurologic GD phenotypes (GD2 and GD3), the patients in this investigation were identified as having non-neuronopathic GD1. The other mutation, p. Leu303Ile, is a new GD-related mutation not indexed in PubMed that enriches the GBA1 gene mutation spectrum. Biosignature analysis has shown that both mutations alter the protein's three-dimensional structure, which may be a pathogenic mechanism for GD1 in this patient.

Gut-Brain Axis Modulation of Metabolic Disorders: Exploring the Intertwined Neurohumoral Pathways and Therapeutic Prospects.

A significant rise in metabolic disorders, frequently brought on by lifestyle choices, is alarming. A wide range of preliminary studies indicates the significance of the gut-brain axis, which regulates bidirectional signaling between the gastrointestinal tract and the cognitive system, and is crucial for regulating host metabolism and cognition. Intimate connections between the brain and the gastrointestinal tract provide a network of neurohumoral transmission that can transmit in both directions. The gut-brain axis successfully establishes that the wellness of the brain is always correlated with the extent to which the gut operates. Research on the gut-brain axis has historically concentrated on how psychological health affects how well the gastrointestinal system works. The latest studies, however, revealed that the gut microbiota interacts with the brain via the gut-brain axis to control phenotypic changes in the brain and in behavior. This study addresses the significance of the gut microbiota, the role of the gut-brain axis in management of various metabolic disorders, the hormonal and neural signaling pathways and the therapeutic treatments available. Its objective is to establish the significance of the gut-brain axis in metabolic disorders accurately and examine the link between the two while evaluating the therapeutic strategies to be incorporated in the future.

Neuronopathic Gaucher disease: Rare in the West, common in the East.

Gaucher disease (GD) stands as one of the most prevalent lysosomal disorders, yet neuronopathic GD (nGD) is an uncommon subset characterized by a wide array of clinical manifestations that complicate diagnosis, particularly when neurological symptoms are understated. nGD may manifest as the acute neuronopathic type, or GD type 2 (GD2), either prenatally or within the first weeks to months of life, whereas GD type 3 (GD3) symptoms may emerge at any point during childhood or occasionally in adolescence. The clinical presentation encompasses severe systemic involvement to mild visceral disease, often coupled with a spectrum of progressive neurological signs and symptoms such as cognitive impairment, ataxia, seizures, myoclonus, varying degrees of brainstem dysfunction presenting with stridor, apneic episodes, and/or impaired swallowing. This manuscript aims to provide a comprehensive review of the incidence, distinctive presentations, and diverse clinical phenotypes of nGD across various countries and regions. It will explore the natural history of the neurodegenerative process in GD, shedding light on its various manifestations during infancy and childhood, and offer insights into the diagnostic journey, the challenges faced in the clinical management, and current and investigative therapeutic approaches for GD's neurological variants.

Validity of the Short Weekly Calendar Planning Activity in patients with Parkinson disease and nonmanifesting LRRK2 and GBA carriers.

BACKGROUND AND PURPOSE: Subtle executive dysfunction is common in people newly diagnosed with Parkinson disease (PD), even when general cognitive abilities are intact. This study examined the Short Weekly Calendar Planning Activity (WCPA-10)'s known-group construct validity, comparing persons with PD to healthy controls (HCs) and nonmanifesting carriers of LRRK2 and GBA gene mutations to HCs. Additionally, convergent and ecological validity was examined. METHODS: The study included 73 participants: 22 with idiopathic PD (iPD) who do not carry any of the founder GBA mutations or LRRK2-G2019S, 29 nonmanifesting carriers of the G2019S-LRRK2 (n = 14) and GBA (n = 15) mutations, and 22 HCs. Known-group validity was determined using the WCPA-10, convergent validity by also using the Montreal Cognitive Assessment (MoCA) and Color Trails Test (CTT), and ecological validity by using the WCPA-10, Schwab and England Activities of Daily Living Scale (SE ADL), and Physical Activity Scale for the Elderly (PASE). RESULTS: Known-group validity of the WCPA-10 was established for the iPD group only; they followed fewer rules (p = 0.020), were slower (p = 0.003) and less efficient (p = 0.001), used more strategies (p = 0.017) on the WCPA-10, and achieved significantly lower CTT scores (p < 0.001) than the HCs. The nonmanifesting carriers and HCs were similar on all cognitive tests. Convergent and ecological validity of the WCPA-10 were partially established, with few correlations between WCPA-10 outcome measures and the MoCA (r = 0.50, r = 0.41), CTT-2 (r = 0.43), SE ADL (r = 0.41), and PASE (r = 0.54, r = 0.46, r = 0.31). CONCLUSIONS: This study affirms the known-group validity for most (four) WCPA-10 scores and partially confirms its convergent and ecological validity for PD.

Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation.

BACKGROUND: To date, no disease modifying therapies are available for Parkinson's disease (PD). Since PD is the second most prevalent neurodegenerative disorder, there is a high demand for such therapies. Both environmental and genetic risk factors play an important role in the etiology and progression of PD. The most common genetic risk factor for PD is a mutation in the GBA1(GBA)-gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). The mucolytic ambroxol is a repurposed drug, which has shown the property to upregulate GCase activity in-vitro and in-vivo. Ambroxol therefore has the potency to become a disease modifying therapy in PD, which was the reason to design this randomized controlled trial with ambroxol in PD patients. METHODS: This trial is a single-center, double-blind, randomized, placebo-controlled study, including 80 PD patients with a GBA mutation, receiving either ambroxol 1800 mg/day or placebo for 48 weeks. The primary outcome measure is the Unified Parkinson's Disease Rating Scale motor subscore (part III) of the Movement Disorder Society (MDS-UPDRSIII) in the practically defined off-state at 60 weeks (after a 12-week washout period). Secondary outcomes include a 3,4-dihydroxy-6-18F-fluoro-I-phenylalanine ([18F]FDOPA) PET-scan of the brain, Magnetic Resonance Imaging (with resting state f-MRI and Diffusion Tensor Imaging), GCase activity, both intra- and extracellularly, sphingolipid profiles in plasma, Montreal Cognitive Assessment (MoCA), quality of life (QoL) measured by the Parkinson's Disease Questionnaire (PDQ-39) and the Non-Motor Symptom Scale (NMSS) questionnaire. DISCUSSION: Ambroxol up to 1200 mg/day has shown effects on human cerebrospinal fluid endpoints, which supports at least passage of the blood-brain-barrier. The dose titration in this trial up to 1800 mg/day will reveal if this dose level is safe and also effective in modifying the course of the disease. TRIAL REGISTRATION: NCT05830396. Registration date: March 20, 2023.

GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson's disease.

The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson's Progression Markers Initiative study, followed by a meta-analysis with a total of 976 PD patients and 478 controls with available data on galactosylceramidase activity. We further analysed the effects of common GALC variants on expression and galactosylceramidase activity using genomic colocalization methods. Mendelian randomization was used to study whether galactosylceramidase activity may be causal in PD. To study the role of rare GALC variants, we analysed sequencing data from 5028 PD patients and 5422 controls. Additionally, we studied the functional impact of GALC knockout on alpha-synuclein accumulation and on glucocerebrosidase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered galactosylceramidase activity. The top hit in PD genome-wide association study in the GALC locus, rs979812, is associated with increased galactosylceramidase activity (b = 1.2; SE = 0.06; P = 5.10 × 10-95). No other variants outside the GALC locus were associated with galactosylceramidase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased galactosylceramidase expression. Mendelian randomization suggested that increased galactosylceramidase activity may be causally associated with PD (b = 0.025, SE = 0.007, P = 0.0008). We did not find an association between rare GALC variants and PD. GALC knockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced galactosylceramidase levels may be associated with PD. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of galactosylceramidase affecting its activity. Our results nominate GALC as the gene associated with PD in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing galactosylceramidase expression and activity. Whether altering galactosylceramidase activity could be considered as a therapeutic target should be further studied.