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Nature Communications Feb 2024Comorbid proteinopathies are observed in many neurodegenerative disorders including Alzheimer's disease (AD), increase with age, and influence clinical outcomes, yet the...
Comorbid proteinopathies are observed in many neurodegenerative disorders including Alzheimer's disease (AD), increase with age, and influence clinical outcomes, yet the mechanisms remain ill-defined. Here, we show that reduction of progranulin (PGRN), a lysosomal protein associated with TDP-43 proteinopathy, also increases tau inclusions, causes concomitant accumulation of α-synuclein and worsens mortality and disinhibited behaviors in tauopathy mice. The increased inclusions paradoxically protect against spatial memory deficit and hippocampal neurodegeneration. PGRN reduction in male tauopathy attenuates activity of β-glucocerebrosidase (GCase), a protein previously associated with synucleinopathy, while increasing glucosylceramide (GlcCer)-positive tau inclusions. In neuronal culture, GCase inhibition enhances tau aggregation induced by AD-tau. Furthermore, purified GlcCer directly promotes tau aggregation in vitro. Neurofibrillary tangles in human tauopathies are also GlcCer-immunoreactive. Thus, in addition to TDP-43, PGRN regulates tau- and synucleinopathies via GCase and GlcCer. A lysosomal PGRN-GCase pathway may be a common therapeutic target for age-related comorbid proteinopathies.
Topics: Male; Humans; Mice; Animals; alpha-Synuclein; Progranulins; Glucosylceramidase; tau Proteins; Tauopathies; Alzheimer Disease; Proteostasis Deficiencies
PubMed: 38365772
DOI: 10.1038/s41467-024-45692-3 -
Communications Biology Apr 2023Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild...
Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.
Topics: Humans; Gaucher Disease; Glucosylceramidase; Hippo Signaling Pathway; Neurons; Cell Proliferation
PubMed: 37076591
DOI: 10.1038/s42003-023-04813-2 -
Nature Communications Apr 2023Mutations in glucocerebrosidase cause the lysosomal storage disorder Gaucher's disease and are the most common risk factor for Parkinson's disease. Therapies to restore...
Mutations in glucocerebrosidase cause the lysosomal storage disorder Gaucher's disease and are the most common risk factor for Parkinson's disease. Therapies to restore the enzyme's function in the brain hold great promise for treating the neurological implications. Thus, we developed blood-brain barrier penetrant therapeutic molecules by fusing transferrin receptor-binding moieties to β-glucocerebrosidase (referred to as GCase-BS). We demonstrate that these fusion proteins show significantly increased uptake and lysosomal efficiency compared to the enzyme alone. In a cellular disease model, GCase-BS rapidly rescues the lysosomal proteome and lipid accumulations beyond known substrates. In a mouse disease model, intravenous injection of GCase-BS leads to a sustained reduction of glucosylsphingosine and can lower neurofilament-light chain plasma levels. Collectively, these findings demonstrate the potential of GCase-BS for treating GBA1-associated lysosomal dysfunction, provide insight into candidate biomarkers, and may ultimately open a promising treatment paradigm for lysosomal storage diseases extending beyond the central nervous system.
Topics: Animals; Mice; Gaucher Disease; Glucosylceramidase; Brain; Neurons; Parkinson Disease; Lysosomes; Mutation; alpha-Synuclein
PubMed: 37045813
DOI: 10.1038/s41467-023-37632-4 -
Genes Mar 2024Gaucher disease, an autosomal recessively inherited lysosomal storage disorder, results from biallelic mutations in the gene resulting in deficient activity of the... (Review)
Review
Gaucher disease, an autosomal recessively inherited lysosomal storage disorder, results from biallelic mutations in the gene resulting in deficient activity of the enzyme glucocerebrosidase. In Gaucher disease, the reduced levels and activity of glucocerebrosidase lead to a disparity in the rates of formation and breakdown of glucocerebroside and glucosylsphingosine, resulting in the accumulation of these lipid substrates in the lysosome. This gives rise to the development of Gaucher cells, engorged macrophages with a characteristic wrinkled tissue paper appearance. There are both non-neuronopathic (type 1) and neuronopathic (types 2 and 3) forms of Gaucher disease, associated with varying degrees of severity. The visceral and hematologic manifestations of Gaucher disease respond well to both enzyme replacement therapy and substrate reduction therapy. However, these therapies do not improve the neuronopathic manifestations, as they cannot cross the blood-brain barrier. There is now an established precedent for treating lysosomal storage disorders with gene therapy strategies, as many have the potential to cross into the brain. The range of the gene therapies being employed is broad, but this review aimed to discuss the progress, advances, and challenges in developing viral gene therapy as a treatment for Gaucher disease.
Topics: Humans; Gaucher Disease; Glucosylceramidase; Brain; Blood-Brain Barrier; Macrophages
PubMed: 38540423
DOI: 10.3390/genes15030364 -
The FEBS Journal Oct 2018GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), an enzyme involved in sphingolipid metabolism. Mutations in the GBA gene are numerically the most important... (Review)
Review
GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), an enzyme involved in sphingolipid metabolism. Mutations in the GBA gene are numerically the most important risk factor for developing Parkinson disease (PD) accounting for at least 5% of all PD cases. Furthermore, loss of GCase activity is found in sporadic PD brains. Lysosomal dysfunction is thought to play a principal role in PD pathogenesis and in particular its effect on the metabolism of α-synuclein. A hallmark of PD is the presence of intraneuronal protein inclusions called Lewy bodies, which are composed mainly of α-synuclein. Cellular and animal models of GCase deficiency result in lysosomal dysfunction, and in particular the autophagy lysosome pathway, resulting in the accumulation of α-synuclein. Some forms of mutant GCase unfold in the endoplasmic reticulum activating the unfolded protein response, which might also contribute to PD pathogenesis. It has also been suggested that accumulation of GCase substrates glucosylceramide/glucosylsphingosine may contribute to GBA-PD pathogenesis. Mitochondrial dysfunction and neuroinflammation are associated with GCase deficiency and have also been implicated in the aetiology of PD. This review discusses these points and highlights potential treatments that might be effective in treating GCase deficiency in PD.
Topics: Animals; Gene Expression Regulation, Enzymologic; Glucosylceramidase; Humans; Inflammation; Mitochondria; Mutation; Parkinson Disease
PubMed: 29385658
DOI: 10.1111/febs.14393 -
Biophysical Chemistry Jun 2021Mutations in the gene GBA, encoding glucocerebrosidase (GCase), are the highest genetic risk factor for Parkinson's disease (PD). GCase is a lysosomal glycoprotein... (Review)
Review
Mutations in the gene GBA, encoding glucocerebrosidase (GCase), are the highest genetic risk factor for Parkinson's disease (PD). GCase is a lysosomal glycoprotein responsible for the hydrolysis of glucosylceramide into glucose and ceramide. Mutations in GBA cause a decrease in GCase activity, stability and protein levels which in turn lead to the accumulation of GCase lipid substrates as well as α-synuclein (αS) in vitro and in vivo. αS is the main constituent of Lewy bodies found in the brain of PD patients and an increase in its levels was found to be associated with a decrease in GCase activity/protein levels in vitro and in vivo. In this review, we describe the reported biophysical and biochemical changes that GBA mutations can induce in GCase activity and stability as well as the current overview of the levels of GCase protein/activity, αS and lipids measured in patient-derived samples including post-mortem brains, stem cell-derived neurons, cerebrospinal fluid, blood and fibroblasts as well as in SH-SY5Y cells. In particular, we report how the levels of αS and lipids are affected by/correlated to significant changes in GCase activity/protein levels and which cellular pathways are activated or disrupted by these changes in each model. Finally, we review the current strategies used to revert the changes in the levels of GCase activity/protein, αS and lipids in the context of PD.
Topics: Glucosylceramidase; Humans; Lipids; Models, Molecular; Parkinson Disease; alpha-Synuclein
PubMed: 33832803
DOI: 10.1016/j.bpc.2020.106534 -
Chembiochem : a European Journal of... Nov 2021Glucocerebrosidase (GBA), a lysosomal retaining β-d-glucosidase, has recently been shown to hydrolyze β-d-xylosides and to transxylosylate cholesterol. Genetic defects...
Glucocerebrosidase (GBA), a lysosomal retaining β-d-glucosidase, has recently been shown to hydrolyze β-d-xylosides and to transxylosylate cholesterol. Genetic defects in GBA cause the lysosomal storage disorder Gaucher disease (GD), and also constitute a risk factor for developing Parkinson's disease. GBA and other retaining glycosidases can be selectively visualized by activity-based protein profiling (ABPP) using fluorescent probes composed of a cyclophellitol scaffold having a configuration tailored to the targeted glycosidase family. GBA processes β-d-xylosides in addition to β-d-glucosides, this in contrast to the other two mammalian cellular retaining β-d-glucosidases, GBA2 and GBA3. Here we show that the xylopyranose preference also holds up for covalent inhibitors: xylose-configured cyclophellitol and cyclophellitol aziridines selectively react with GBA over GBA2 and GBA3 in vitro and in vivo, and that the xylose-configured cyclophellitol is more potent and more selective for GBA than the classical GBA inhibitor, conduritol B-epoxide (CBE). Both xylose-configured cyclophellitol and cyclophellitol aziridine cause accumulation of glucosylsphingosine in zebrafish embryo, a characteristic hallmark of GD, and we conclude that these compounds are well suited for creating such chemically induced GD models.
Topics: Animals; Cells, Cultured; Cyclohexanols; Enzyme Inhibitors; Glucosylceramidase; HEK293 Cells; Humans; Molecular Conformation; Xylose; Zebrafish
PubMed: 34459538
DOI: 10.1002/cbic.202100396 -
Neurodegenerative Disease Management 2016
Topics: Clinical Studies as Topic; Genetic Predisposition to Disease; Glucosylceramidase; Humans; Mutation; Parkinsonian Disorders; Risk Factors
PubMed: 26782311
DOI: 10.2217/nmt.15.68 -
Blood Aug 2011This review presents a cohesive approach to treating patients with Gaucher disease. The spectrum of the clinical presentation of the disease is broad, yet heretofore... (Review)
Review
This review presents a cohesive approach to treating patients with Gaucher disease. The spectrum of the clinical presentation of the disease is broad, yet heretofore there was only one disease-specific treatment. In the past 2 years, a global shortage of this product has resulted in reassessment of the "one enzyme-one disease-one therapy" mantra. It has also showcased the multiple levels that engage the patient, the treating physician, and the third-party insurer in providing adequate treatment to all symptomatic patients. The key points summarizing the way I manage my patients include accurate enzymatic diagnosis with mutation analysis (for some prognostication and better carrier detection in the family), a detailed follow-up every 6-12 months (with an option to see consultants and attention to comorbidities), and initiation of enzyme replacement therapy according to symptoms or deterioration in clinically significant features or both. I do not treat patients with very mild disease, but I consider presymptomatic therapy for patients at risk, including young women with poor obstetric history. I prefer the minimal-effective dose rather than the maximally tolerated dose, and when the difference between high-dose and lower-dose regimens is (merely statistically significant but) clinically meaningless, minimizing the burden on society by advocating less-expensive treatments is ethically justified.
Topics: DNA Mutational Analysis; Enzyme Replacement Therapy; Follow-Up Studies; Gaucher Disease; Genetic Counseling; Genotype; Glucosylceramidase; Humans; Mutation
PubMed: 21670466
DOI: 10.1182/blood-2011-04-308890 -
Disease Models & Mechanisms Jun 2023Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients...
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.
Topics: Animals; Glucosylceramidase; Zebrafish; Niemann-Pick Disease, Type A; Parkinson Disease; Phenotype; alpha-Synuclein; Mutation
PubMed: 36951087
DOI: 10.1242/dmm.049954