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Neurobiology of Disease Oct 2020While glia are essential for regulating the homeostasis in the normal brain, their dysfunction contributes to neurodegeneration in many brain diseases, including... (Review)
Review
While glia are essential for regulating the homeostasis in the normal brain, their dysfunction contributes to neurodegeneration in many brain diseases, including Parkinson's disease (PD). Recent studies have identified that PD-associated genes are expressed in glial cells as well as neurons and have crucial roles in microglia and astrocytes. Here, we discuss the role of microglia and astrocytes dysfunction in relation to PD-linked mutations and their implications in PD pathogenesis. A better understanding of microglia and astrocyte functions in PD may provide insights into neurodegeneration and novel therapeutic approaches for PD.
Topics: Astrocytes; Glucosylceramidase; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Microglia; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Ubiquitin-Protein Ligases; alpha-Synuclein
PubMed: 32736085
DOI: 10.1016/j.nbd.2020.105028 -
Cells Apr 2022The gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5-15% of PD patients have mutations... (Review)
Review
The gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5-15% of PD patients have mutations in the gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, -associated PD is identical to sporadic PD, aside from the earlier age at onset (AAO), more frequent cognitive impairment and more rapid progression. Mutations in can be associated with loss- and gain-of-function mechanisms. A key hallmark of PD is the presence of intraneuronal proteinaceous inclusions named Lewy bodies, which are made up primarily of alpha-synuclein. Mutations in the gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism. Models of GCase deficiency demonstrate dysfunction of the autophagic-lysosomal pathway and subsequent accumulation of alpha-synuclein. This dysfunction can also lead to aberrant lipid metabolism, including the accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine. Certain mutations cause GCase to be misfolded and retained in the endoplasmic reticulum (ER), activating stress responses including the unfolded protein response (UPR), which may contribute to neurodegeneration. In addition to these mechanisms, a GCase deficiency has also been associated with mitochondrial dysfunction and neuroinflammation, which have been implicated in the pathogenesis of PD. This review discusses the pathways associated with -PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration.
Topics: Endoplasmic Reticulum; Glucosylceramidase; Humans; Lysosomes; Mutation; Parkinson Disease; alpha-Synuclein
PubMed: 35455941
DOI: 10.3390/cells11081261 -
Turkish Journal of Haematology :... Jun 2022Gaucher disease (GD) is a rare hereditary lysosomal storage disease that arises due to deficiency of glucocerebrosidase. Early diagnosis is very important for starting... (Review)
Review
Gaucher disease (GD) is a rare hereditary lysosomal storage disease that arises due to deficiency of glucocerebrosidase. Early diagnosis is very important for starting proper treatment and preventing complications. Splenomegaly, anemia, and thrombocytopenia are the most common findings in GD and so most patients are initially referred to hematologists. The Turkish Society of Hematology established its Rare Hematological Diseases Subcommittee in 2015. One of the main topics of this subcommittee was to increase and improve awareness and education of rare diseases among hematologists in Turkey. This review presents GD with an overview of its clinical features, pathophysiology, and treatment options for hematologists.
Topics: Anemia; Gaucher Disease; Glucosylceramidase; Humans; Splenomegaly; Thrombocytopenia; Turkey
PubMed: 35439918
DOI: 10.4274/tjh.galenos.2021.2021.0683 -
Pathobiology : Journal of... 2016We present a brief review of Gaucher disease (GD), the most common lysosomal storage disease. GD is a rare autosomal recessive disorder characterized by the defective... (Review)
Review
We present a brief review of Gaucher disease (GD), the most common lysosomal storage disease. GD is a rare autosomal recessive disorder characterized by the defective function of the catabolic enzyme β-glucocerebrosidase (GBA), leading to an accumulation of its substrate, glucocerebroside. Clinical signs and symptoms include neurological dysfunctions, bone infarcts and malformations, hepatosplenomegaly and hypersplenism leading to anemia, neutropenia and thrombocytopenia. Enzyme replacement therapy with recombinant GBA is the mainstay of treatment for GD, which became the first successfully managed lipid storage disease. Future treatments may include oral enzyme replacement and/or gene therapy interventions.
Topics: Enzyme Replacement Therapy; Gaucher Disease; Genetic Therapy; Glucosylceramidase; Humans; Hypersplenism; Splenomegaly
PubMed: 26588331
DOI: 10.1159/000440865 -
Molecular Genetics and Metabolism Feb 2021Gaucher disease (GD), resulting from biallelic mutations in the gene GBA1, is a monogenic recessively inherited Mendelian disorder with a wide range of phenotypic... (Review)
Review
Gaucher disease (GD), resulting from biallelic mutations in the gene GBA1, is a monogenic recessively inherited Mendelian disorder with a wide range of phenotypic presentations. The more severe forms of the disease, acute neuronopathic GD (GD2) and chronic neuronopathic GD (GD3), also have a continuum of disease severity with an overlap in manifestations and limited genotype-phenotype correlation. In very young patients, assigning a definitive diagnosis can sometimes be challenging. Several recent studies highlight specific features of neuronopathic GD that may provide diagnostic clues. Distinguishing between the different GD types has important therapeutic implications. Currently there are limited treatment options specifically for neuronopathic GD due to the difficulty in delivering therapies across the blood-brain barrier. In this work, we present both classic and newly appreciated aspects of the Gaucher phenotype that can aid in discriminating between acute and chronic neuronopathic GD, and highlight the continuing therapeutic challenges.
Topics: Blood-Brain Barrier; Gaucher Disease; Genetic Association Studies; Glucosylceramidase; Humans; Phenotype; Severity of Illness Index
PubMed: 33483255
DOI: 10.1016/j.ymgme.2021.01.002 -
Cells Apr 2019Parkinson's disease (PD) is the second most common degenerative disorder. Although the disease was described more than 200 years ago, its pathogenetic mechanisms have... (Review)
Review
Parkinson's disease (PD) is the second most common degenerative disorder. Although the disease was described more than 200 years ago, its pathogenetic mechanisms have not yet been fully described. In recent years, the discovery of the association between mutations of the gene (encoding for the lysosomal enzyme glucocerebrosidase) and PD facilitated a better understating of this disorder. mutations are the most common genetic risk factor of the disease. However, mutations of this gene can be found in different phenotypes, such as Gaucher's disease (GD), PD, dementia with Lewy bodies (DLB) and rapid eye movements (REM) sleep behavior disorders (RBDs). Understanding the pathogenic role of this mutation and its different manifestations is crucial for geneticists and scientists to guide their research and to select proper cohorts of patients. Moreover, knowing the implications of the mutation in the context of PD and the other associated phenotypes is also important for clinicians to properly counsel their patients and to implement their care. With the present review we aim to describe the genetic, clinical, and therapeutic features related to the mutation of the gene.
Topics: Gaucher Disease; Glucosylceramidase; Humans; Lewy Body Disease; Mutation; Parkinson Disease; Phenotype; Risk Factors
PubMed: 31010158
DOI: 10.3390/cells8040364 -
Journal of Parkinson's Disease 2021Human genetic studies as well as studies in animal models indicate that lysosomal dysfunction plays a key role in the pathogenesis of Parkinson's disease. Among the... (Review)
Review
Human genetic studies as well as studies in animal models indicate that lysosomal dysfunction plays a key role in the pathogenesis of Parkinson's disease. Among the lysosomal genes involved, GBA1 has the largest impact on Parkinson's disease risk. Deficiency in the GBA1 encoded enzyme glucocerebrosidase (GCase) leads to the accumulation of the GCase glycolipid substrates glucosylceramide and glucosylsphingosine and ultimately results in toxicity and inflammation and negatively affect many clinical aspects of Parkinson's disease, including disease risk, the severity of presentation, age of onset, and likelihood of progression to dementia. These findings support the view that re-establishing normal levels of GCase enzyme activity may reduce the progression of Parkinson's disease in patients carrying GBA1 mutations. Studies in mouse models indicate that PR001, a AAV9 vector-based gene therapy designed to deliver a functional GBA1 gene to the brain, suggest that this therapeutic approach may slow or stop disease progression. PR001 is currently being evaluated in clinical trials with Parkinson's disease patients carrying GBA1 mutations.
Topics: Animals; Gaucher Disease; Genetic Therapy; Glucosylceramidase; Humans; Lysosomes; Mice; Mutation; Parkinson Disease; alpha-Synuclein
PubMed: 34151863
DOI: 10.3233/JPD-212739 -
TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease.Neuron Dec 2021Impairment in glucocerebrosidase (GCase) is strongly associated with the development of Parkinson's disease (PD), yet the regulators responsible for its impairment...
Impairment in glucocerebrosidase (GCase) is strongly associated with the development of Parkinson's disease (PD), yet the regulators responsible for its impairment remain elusive. In this paper, we identify the E3 ligase Thyroid Hormone Receptor Interacting Protein 12 (TRIP12) as a key regulator of GCase. TRIP12 interacts with and ubiquitinates GCase at lysine 293 to control its degradation via ubiquitin proteasomal degradation. Ubiquitinated GCase by TRIP12 leads to its functional impairment through premature degradation and subsequent accumulation of α-synuclein. TRIP12 overexpression causes mitochondrial dysfunction, which is ameliorated by GCase overexpression. Further, conditional TRIP12 knockout in vitro and knockdown in vivo promotes the expression of GCase, which blocks α-synuclein preformed fibrils (α-syn PFFs)-provoked dopaminergic neurodegeneration. Moreover, TRIP12 accumulates in human PD brain and α-synuclein-based mouse models. The identification of TRIP12 as a regulator of GCase provides a new perspective on the molecular mechanisms underlying dysfunctional GCase-driven neurodegeneration in PD.
Topics: Animals; Brain; Carrier Proteins; Disease Models, Animal; Glucosylceramidase; Mice; Parkinson Disease; Ubiquitin-Protein Ligases; Ubiquitination; alpha-Synuclein
PubMed: 34644545
DOI: 10.1016/j.neuron.2021.09.031 -
Annals of Neurology Mar 2022This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic...
OBJECTIVE
This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease.
METHODS
Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status.
RESULTS
Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36-60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = -2.35 to -1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = -2.14 to -1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = -1.80 to -1.18).
INTERPRETATION
Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424-435.
Topics: Aged; Cognition; Databases, Factual; Deep Brain Stimulation; Female; Glucosylceramidase; Heterozygote; Humans; Male; Middle Aged; Mutation; Neuropsychological Tests; Parkinson Disease; Subthalamic Nucleus
PubMed: 34984729
DOI: 10.1002/ana.26302 -
Nature Neuroscience Mar 2020Parkinson's disease is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of α-synuclein (α-Syn)...
Parkinson's disease is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of α-synuclein (α-Syn) aggregates. Evidence suggests that α-Syn aggregation can originate in peripheral tissues and progress to the brain via autonomic fibers. We tested this by inoculating the duodenal wall of mice with α-Syn preformed fibrils. Following inoculation, we observed gastrointestinal deficits and physiological changes to the enteric nervous system. Using the AAV-PHP.S capsid to target the lysosomal enzyme glucocerebrosidase for peripheral gene transfer, we found that α-Syn pathology is reduced due to the increased expression of this protein. Lastly, inoculation of α-Syn fibrils in aged mice, but not younger mice, resulted in progression of α-Syn histopathology to the midbrain and subsequent motor defects. Our results characterize peripheral synucleinopathy in prodromal Parkinson's disease and explore cellular mechanisms for the gut-to-brain progression of α-Syn pathology.
Topics: Animals; Brain; Digestive System Diseases; Duodenum; Enteric Nervous System; Glucosylceramidase; Mesencephalon; Mice; Mice, Inbred C57BL; Movement Disorders; Nerve Fibers; Nociception; Nodose Ganglion; Synucleinopathies
PubMed: 32066981
DOI: 10.1038/s41593-020-0589-7