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  1. Article ; Online: Key genes and convergent pathogenic mechanisms in Parkinson disease.

    Coukos, Robert / Krainc, Dimitri

    Nature reviews. Neuroscience

    2024  

    Abstract: Parkinson disease (PD) is a neurodegenerative disorder marked by the preferential dysfunction and death of dopaminergic neurons in the substantia nigra. The onset and progression of PD is influenced by a diversity of genetic variants, many of which lack ... ...

    Abstract Parkinson disease (PD) is a neurodegenerative disorder marked by the preferential dysfunction and death of dopaminergic neurons in the substantia nigra. The onset and progression of PD is influenced by a diversity of genetic variants, many of which lack functional characterization. To identify the most high-yield targets for therapeutic intervention, it is important to consider the core cellular compartments and functional pathways upon which the varied forms of pathogenic dysfunction may converge. Here, we review several key PD-linked proteins and pathways, focusing on the mechanisms of their potential convergence in disease pathogenesis. These dysfunctions primarily localize to a subset of subcellular compartments, including mitochondria, lysosomes and synapses. We discuss how these pathogenic mechanisms that originate in different cellular compartments may coordinately lead to cellular dysfunction and neurodegeneration in PD.
    Language English
    Publishing date 2024-04-10
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2034150-7
    ISSN 1471-0048 ; 1471-0048 ; 1471-003X
    ISSN (online) 1471-0048
    ISSN 1471-0048 ; 1471-003X
    DOI 10.1038/s41583-024-00812-2
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    Zs.A 5473: Show issues Location:
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  2. Article ; Online: Protocol to investigate Parkinson's patient-derived dopaminergic neurons by live-cell microscopy and oxidized dopamine assays.

    Song, Pingping / Krainc, Dimitri

    STAR protocols

    2024  Volume 5, Issue 1, Page(s) 102889

    Abstract: Dopaminergic neurons derived from human induced pluripotent stem cells recapitulate key pathogenic phenotypes observed in Parkinson's disease (PD). Here, we present a protocol to analyze oxidized dopamine and the recruitment of parkin onto synaptic ... ...

    Abstract Dopaminergic neurons derived from human induced pluripotent stem cells recapitulate key pathogenic phenotypes observed in Parkinson's disease (PD). Here, we present a protocol to analyze oxidized dopamine and the recruitment of parkin onto synaptic vesicles in neurons derived from patients with mutations in parkin that cause autosomal recessive PD. We describe steps for neuronal differentiation, live-cell microscopy, detection of oxidized dopamine, and labeling of synaptic vesicles. These protocols can be applied to studies of other forms of genetic and sporadic forms of PD. For complete details on the use and execution of this protocol, please refer to Song et al.
    MeSH term(s) Humans ; Dopamine/pharmacology ; Dopaminergic Neurons ; Parkinson Disease/pathology ; Microscopy ; Induced Pluripotent Stem Cells ; Ubiquitin-Protein Ligases
    Chemical Substances Dopamine (VTD58H1Z2X) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2024-02-10
    Publishing country United States
    Document type Journal Article
    ISSN 2666-1667
    ISSN (online) 2666-1667
    DOI 10.1016/j.xpro.2024.102889
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  3. Article ; Online: Mechanisms of Glucocerebrosidase Dysfunction in Parkinson's Disease.

    Chatterjee, Diptaman / Krainc, Dimitri

    Journal of molecular biology

    2023  Volume 435, Issue 12, Page(s) 168023

    Abstract: Beta-glucocerebrosidase is a lysosomal hydrolase, encoded by GBA1 that represents the most common risk gene associated with Parkinson's disease (PD) and Lewy Body Dementia. Glucocerebrosidase dysfunction has been also observed in the absence of GBA1 ... ...

    Abstract Beta-glucocerebrosidase is a lysosomal hydrolase, encoded by GBA1 that represents the most common risk gene associated with Parkinson's disease (PD) and Lewy Body Dementia. Glucocerebrosidase dysfunction has been also observed in the absence of GBA1 mutations across different genetic and sporadic forms of PD and related disorders, suggesting a broader role of glucocerebrosidase in neurodegeneration. In this review, we highlight recent advances in mechanistic characterization of glucocerebrosidase function as the foundation for development of novel therapeutics targeting glucocerebrosidase in PD and related disorders.
    MeSH term(s) Humans ; alpha-Synuclein/genetics ; Glucosylceramidase/genetics ; Glucosylceramidase/metabolism ; Lysosomes/enzymology ; Mutation ; Parkinson Disease/enzymology ; Parkinson Disease/genetics
    Chemical Substances alpha-Synuclein ; Glucosylceramidase (EC 3.2.1.45) ; GBA protein, human (EC 3.2.1.45)
    Language English
    Publishing date 2023-02-23
    Publishing country Netherlands
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2023.168023
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  4. Article ; Online: Cell biology of Parkinson's disease: Mechanisms of synaptic, lysosomal, and mitochondrial dysfunction.

    Brooker, Sarah M / Naylor, Grace E / Krainc, Dimitri

    Current opinion in neurobiology

    2024  Volume 85, Page(s) 102841

    Abstract: Parkinson's disease (PD) is a growing cause of disability worldwide and there is a critical need for the development of disease-modifying therapies to slow or stop disease progression. Recent advances in characterizing the genetics of PD have expanded ... ...

    Abstract Parkinson's disease (PD) is a growing cause of disability worldwide and there is a critical need for the development of disease-modifying therapies to slow or stop disease progression. Recent advances in characterizing the genetics of PD have expanded our understanding of the cell biology of this disorder. Mitochondrial oxidative stress, defects in synaptic function, and impaired lysosomal activity have been shown to be linked in PD, resulting in a pathogenic feedback cycle involving the accumulation of toxic oxidized dopamine and alpha-synuclein. In this review, we will highlight recent data on a subset of PD-linked genes which have key roles in these pathways and the pathogenic cycle. We will furthermore discuss findings highlighting the importance of dynamic mitochondria-lysosome contact sites that mediate direct inter-organelle cross-talk in the pathogenesis of PD and related disorders.
    MeSH term(s) Humans ; Parkinson Disease/genetics ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism ; Lysosomes/metabolism ; Mitochondria/metabolism ; Mitochondrial Diseases/metabolism ; Mitochondrial Diseases/pathology
    Chemical Substances alpha-Synuclein
    Language English
    Publishing date 2024-02-01
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1078046-4
    ISSN 1873-6882 ; 0959-4388
    ISSN (online) 1873-6882
    ISSN 0959-4388
    DOI 10.1016/j.conb.2024.102841
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  5. Article ; Online: Inhibition of cysteine protease cathepsin Lincreases the level and activity of lysosomal glucocerebrosidase.

    Kim, Myung Jong / Kim, Soojin / Reinheckel, Thomas / Krainc, Dimitri

    JCI insight

    2024  Volume 9, Issue 3

    Abstract: The glucocerebrosidase (GCase) encoded by the GBA1 gene hydrolyzes glucosylceramide (GluCer) to ceramide and glucose in lysosomes. Homozygous or compound heterozygous GBA1 mutations cause the lysosomal storage disease Gaucher disease (GD) due to severe ... ...

    Abstract The glucocerebrosidase (GCase) encoded by the GBA1 gene hydrolyzes glucosylceramide (GluCer) to ceramide and glucose in lysosomes. Homozygous or compound heterozygous GBA1 mutations cause the lysosomal storage disease Gaucher disease (GD) due to severe loss of GCase activity. Loss-of-function variants in the GBA1 gene are also the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Restoring lysosomal GCase activity represents an important therapeutic approach for GBA1-associated diseases. We hypothesized that increasing the stability of lysosomal GCase protein could correct deficient GCase activity in these conditions. However, it remains unknown how GCase stability is regulated in the lysosome. We found that cathepsin L, a lysosomal cysteine protease, cleaves GCase and regulates its stability. In support of these data, GCase protein was elevated in the brain of cathepsin L-KO mice. Chemical inhibition of cathepsin L increased both GCase levels and activity in fibroblasts from patients with GD. Importantly, inhibition of cathepsin L in dopaminergic neurons from a patient GBA1-PD led to increased GCase levels and activity as well as reduced phosphorylated α-synuclein. These results suggest that targeting cathepsin L-mediated GCase degradation represents a potential therapeutic strategy for GCase deficiency in PD and related disorders that exhibit decreased GCase activity.
    MeSH term(s) Humans ; Animals ; Mice ; Glucosylceramidase/genetics ; Cathepsin L/genetics ; Cathepsin L/metabolism ; Cathepsins/metabolism ; Cathepsins/therapeutic use ; Cysteine Proteases/metabolism ; Cysteine Proteases/therapeutic use ; Parkinson Disease/metabolism ; Lysosomes/metabolism
    Chemical Substances Glucosylceramidase (EC 3.2.1.45) ; Cathepsin L (EC 3.4.22.15) ; Cathepsins (EC 3.4.-) ; Cysteine Proteases (EC 3.4.-)
    Language English
    Publishing date 2024-02-08
    Publishing country United States
    Document type Journal Article
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.169594
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  6. Article ; Online: Glucocerebrosidase dysfunction in neurodegenerative disease.

    Brooker, Sarah M / Krainc, Dimitri

    Essays in biochemistry

    2021  Volume 65, Issue 7, Page(s) 873–883

    Abstract: Parkinson's disease (PD) and related neurodegenerative disorders, termed the synucleinopathies, are characterized pathologically by the accumulation of protein aggregates containing α-synuclein (aSyn), resulting in progressive neuronal loss. There is ... ...

    Abstract Parkinson's disease (PD) and related neurodegenerative disorders, termed the synucleinopathies, are characterized pathologically by the accumulation of protein aggregates containing α-synuclein (aSyn), resulting in progressive neuronal loss. There is considerable need for the development of neuroprotective strategies to halt or slow disease progression in these disorders. To this end, evaluation of genetic mutations associated with the synucleinopathies has helped to elucidate crucial mechanisms of disease pathogenesis, revealing key roles for lysosomal and mitochondrial dysfunction. The GBA1 gene, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase) is the most common genetic risk factor for PD and is also linked to other neurodegenerative disorders including dementia with Lewy bodies (DLB). Additionally, homozygous mutations in GBA1 are associated with the rare lysosomal storage disorder, Gaucher's disease (GD). In this review, we discuss the current knowledge in the field regarding the diverse roles of GCase in neurons and the multifactorial effects of loss of GCase enzymatic activity. Importantly, GCase has been shown to have a bidirectional relationship with aSyn, resulting in a pathogenic feedback loop that can lead to progressive aSyn accumulation. Alterations in GCase activity have furthermore been linked to multiple distinct pathways involved in neurodegeneration, and therefore GCase has emerged as a promising target for therapeutic drug development for PD and related neurodegenerative disorders, particularly DLB.
    MeSH term(s) Gaucher Disease/complications ; Gaucher Disease/genetics ; Gaucher Disease/metabolism ; Glucosylceramidase/genetics ; Glucosylceramidase/metabolism ; Humans ; Lysosomes/metabolism ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism
    Chemical Substances alpha-Synuclein ; Glucosylceramidase (EC 3.2.1.45)
    Language English
    Publishing date 2021-09-16
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ISSN 1744-1358 ; 0071-1365
    ISSN (online) 1744-1358
    ISSN 0071-1365
    DOI 10.1042/EBC20210018
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  7. Article ; Online: A GNAI1 Pathogenic Variant in a Case with GNAO1-Isolated Dystonia: A Modifier of Disease Severity?

    Monje, Mariana H G / Blackburn, Joanna Sarah / Kinsley, Lisa / Krainc, Dimitri / Mencacci, Niccolò E

    Movement disorders : official journal of the Movement Disorder Society

    2024  

    Language English
    Publishing date 2024-02-28
    Publishing country United States
    Document type Letter
    ZDB-ID 607633-6
    ISSN 1531-8257 ; 0885-3185
    ISSN (online) 1531-8257
    ISSN 0885-3185
    DOI 10.1002/mds.29765
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    Zs.A 2555: Show issues Location:
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    Zs.MO 238: Show issues

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  8. Article ; Online: VPS13C regulates phospho-Rab10-mediated lysosomal function in human dopaminergic neurons.

    Schrӧder, Leonie F / Peng, Wesley / Gao, Ge / Wong, Yvette C / Schwake, Michael / Krainc, Dimitri

    The Journal of cell biology

    2024  Volume 223, Issue 5

    Abstract: Loss-of-function mutations in VPS13C are linked to early-onset Parkinson's disease (PD). While VPS13C has been previously studied in non-neuronal cells, the neuronal role of VPS13C in disease-relevant human dopaminergic neurons has not been elucidated. ... ...

    Abstract Loss-of-function mutations in VPS13C are linked to early-onset Parkinson's disease (PD). While VPS13C has been previously studied in non-neuronal cells, the neuronal role of VPS13C in disease-relevant human dopaminergic neurons has not been elucidated. Using live-cell microscopy, we investigated the role of VPS13C in regulating lysosomal dynamics and function in human iPSC-derived dopaminergic neurons. Loss of VPS13C in dopaminergic neurons disrupts lysosomal morphology and dynamics with increased inter-lysosomal contacts, leading to impaired lysosomal motility and cellular distribution, as well as defective lysosomal hydrolytic activity and acidification. We identified Rab10 as a phospho-dependent interactor of VPS13C on lysosomes and observed a decreased phospho-Rab10-mediated lysosomal stress response upon loss of VPS13C. These findings highlight an important role of VPS13C in regulating lysosomal homeostasis in human dopaminergic neurons and suggest that disruptions in Rab10-mediated lysosomal stress response contribute to disease pathogenesis in VPS13C-linked PD.
    MeSH term(s) Humans ; Dopaminergic Neurons/cytology ; Homeostasis ; Hydrolysis ; Induced Pluripotent Stem Cells ; Lysosomes ; Proteins ; rab GTP-Binding Proteins/genetics
    Chemical Substances Proteins ; rab GTP-Binding Proteins (EC 3.6.5.2) ; Rab10 protein, human (EC 3.6.1.-) ; VPS13C protein, human
    Language English
    Publishing date 2024-02-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.202304042
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  9. Article ; Online: Alterations in Blood Methylome as Potential Epigenetic Biomarker in Sporadic Parkinson's Disease.

    Gonzalez-Latapi, Paulina / Bustos, Bernabe / Dong, Siyuan / Lubbe, Steven / Simuni, Tanya / Krainc, Dimitri

    Annals of neurology

    2024  

    Abstract: Objective: To characterize DNA methylation (DNAm) differences between sporadic Parkinson's disease (PD) and healthy control (HC) individuals enrolled in the Parkinson's Progression Markers Initiative (PPMI).: Methods: Using whole blood, we ... ...

    Abstract Objective: To characterize DNA methylation (DNAm) differences between sporadic Parkinson's disease (PD) and healthy control (HC) individuals enrolled in the Parkinson's Progression Markers Initiative (PPMI).
    Methods: Using whole blood, we characterized longitudinal differences in DNAm between sporadic PD patients (n = 196) and HCs (n = 86) enrolled in PPMI. RNA sequencing (RNAseq) was used to conduct gene expression analyses for genes mapped to differentially methylated cytosine-guanine sites (CpGs).
    Results: At the time of patient enrollment, 5,178 CpGs were differentially methylated (2,683 hypermethylated and 2,495 hypomethylated) in PD compared to HC. Of these, 579 CpGs underwent significant methylation changes over 3 years. Several differentially methylated CpGs were found near the cytochrome P450 family 2 subfamily E member 1 (CYP2E1) gene. Additionally, multiple hypermethylated CpGs were associated with the N-myc downregulated gene family member 4 (NDRG4) gene. RNA-Seq analyses showed 75 differentially expressed genes in PD patients compared to controls. An integrative analysis of both differentially methylated sites and differentially expressed genes revealed 20 genes that exhibited hypomethylation concomitant with overexpression. Additionally, 1 gene, cathepsin H (CTSH), displayed hypermethylation that was associated with its decreased expression.
    Interpretation: We provide initial evidence of alterations in DNAm in blood of PD patients that may serve as potential epigenetic biomarker of disease. To evaluate the significance of these changes throughout the progression of PD, additional profiling at longer intervals and during the prodromal stages of disease will be necessary. ANN NEUROL 2024.
    Language English
    Publishing date 2024-04-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80362-5
    ISSN 1531-8249 ; 0364-5134
    ISSN (online) 1531-8249
    ISSN 0364-5134
    DOI 10.1002/ana.26923
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  10. Article ; Online: Fostering Academia-Industry Partnerships to Facilitate Therapeutic Discoveries in Neurology: The Role of ANA as a Catalyst.

    Ross, M Elizabeth / Krainc, Dimitri / Guo, Ming / Mouradian, M Maral / Ratan, Rajiv R

    Annals of neurology

    2024  Volume 95, Issue 5, Page(s) 825–826

    MeSH term(s) Humans ; Neurology ; Drug Industry ; Biomedical Research ; Academia
    Language English
    Publishing date 2024-03-04
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80362-5
    ISSN 1531-8249 ; 0364-5134
    ISSN (online) 1531-8249
    ISSN 0364-5134
    DOI 10.1002/ana.26904
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