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  1. Article ; Online: Suzanne Pfeffer: sorting through membrane trafficking. Interview by Caitlin Sedwick.

    Pfeffer, Suzanne

    The Journal of cell biology

    2009  Volume 185, Issue 1, Page(s) 4–5

    MeSH term(s) Biological Transport ; California ; Cell Membrane/metabolism ; Protein Transport
    Language English
    Publishing date 2009-04-06
    Publishing country United States
    Document type Interview ; Portrait
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.1851pi
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  2. Article ; Online: Leucine-Rich Repeat Kinases.

    Alessi, Dario R / Pfeffer, Suzanne R

    Annual review of biochemistry

    2024  

    Abstract: Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein kinase that phosphorylates a specific subset of the ∼65 human Rab GTPases, which are ... ...

    Abstract Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein kinase that phosphorylates a specific subset of the ∼65 human Rab GTPases, which are master regulators of the secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose the capacity to bind cognate effector proteins and guanine nucleotide exchange factors. Moreover, the phosphorylated Rabs cannot interact with their cognate prenyl-binding retrieval proteins (also known as guanine nucleotide dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, they gain the capacity to bind phospho-Rab-specific effector proteins, such as RILPL1, with resulting pathological consequences. Rab proteins also act upstream of LRRK2 by controlling its activation and recruitment onto membranes. LRRK2 signaling is counteracted by the phosphoprotein phosphatase PPM1H, which selectively dephosphorylates phospho-Rab proteins. We present here our current understanding of the structure, biochemical properties, and cell biology of LRRK2 and its related paralog LRRK1 and discuss how this information guides the generation of LRRK2 inhibitors for the potential benefit of patients.
    Language English
    Publishing date 2024-04-15
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 207924-0
    ISSN 1545-4509 ; 0066-4154
    ISSN (online) 1545-4509
    ISSN 0066-4154
    DOI 10.1146/annurev-biochem-030122-051144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: LRRK2 phosphorylation of Rab GTPases in Parkinson's disease.

    Pfeffer, Suzanne R

    FEBS letters

    2022  Volume 597, Issue 6, Page(s) 811–818

    Abstract: Rab GTPases comprise a large family of conserved GTPases that are critical regulators of the secretory and endocytic pathways. The human genome encodes ~ 65 Rabs that localize to discrete membrane compartments and, when in their GTP-bound state, bind to ... ...

    Abstract Rab GTPases comprise a large family of conserved GTPases that are critical regulators of the secretory and endocytic pathways. The human genome encodes ~ 65 Rabs that localize to discrete membrane compartments and, when in their GTP-bound state, bind to effector proteins to carry out diverse functions. Activating mutations in LRRK2 kinase cause Parkinson's disease, and subsets of Rab GTPases are important LRRK2 substrates. LRRK2 phosphorylates a conserved threonine residue that is essential for Rab interaction with guanine nucleotide exchange factors, effectors, and GDI that recycles Rabs between membrane compartments. This brief review will highlight new findings related to LRRK2-mediated phosphorylation of Rab GTPases and its consequences. Remarkably, Rab phosphorylation flips a switch on Rab effector selection with dominant consequences for cell pathophysiology.
    MeSH term(s) Humans ; Phosphorylation ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Biological Transport ; Guanine Nucleotide Exchange Factors/metabolism ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism
    Chemical Substances rab GTP-Binding Proteins (EC 3.6.5.2) ; Guanine Nucleotide Exchange Factors ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
    Language English
    Publishing date 2022-09-26
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 212746-5
    ISSN 1873-3468 ; 0014-5793
    ISSN (online) 1873-3468
    ISSN 0014-5793
    DOI 10.1002/1873-3468.14492
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: LRRK2 phosphorylation of Rab GTPases in Parkinson's disease

    Pfeffer, Suzanne R.

    FEBS Letters. 2023 Mar., v. 597, no. 6 p.811-818

    2023  

    Abstract: Rab GTPases comprise a large family of conserved GTPases that are critical regulators of the secretory and endocytic pathways. The human genome encodes ~ 65 Rabs that localize to discrete membrane compartments and, when in their GTP‐bound state, bind to ... ...

    Abstract Rab GTPases comprise a large family of conserved GTPases that are critical regulators of the secretory and endocytic pathways. The human genome encodes ~ 65 Rabs that localize to discrete membrane compartments and, when in their GTP‐bound state, bind to effector proteins to carry out diverse functions. Activating mutations in LRRK2 kinase cause Parkinson's disease, and subsets of Rab GTPases are important LRRK2 substrates. LRRK2 phosphorylates a conserved threonine residue that is essential for Rab interaction with guanine nucleotide exchange factors, effectors, and GDI that recycles Rabs between membrane compartments. This brief review will highlight new findings related to LRRK2‐mediated phosphorylation of Rab GTPases and its consequences. Remarkably, Rab phosphorylation flips a switch on Rab effector selection with dominant consequences for cell pathophysiology.
    Keywords Parkinson disease ; genome ; guanosinetriphosphatase ; humans ; pathophysiology ; phosphorylation ; threonine
    Language English
    Dates of publication 2023-03
    Size p. 811-818.
    Publishing place John Wiley & Sons, Ltd
    Document type Article ; Online
    Note REVIEW
    ZDB-ID 212746-5
    ISSN 1873-3468 ; 0014-5793
    ISSN (online) 1873-3468
    ISSN 0014-5793
    DOI 10.1002/1873-3468.14492
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes.

    Pfeffer, Suzanne R

    The Journal of biological chemistry

    2019  Volume 294, Issue 5, Page(s) 1706–1709

    Abstract: Low-density lipoprotein particles are taken up by cells and delivered to the lysosome where their cholesterol esters are cleaved off by acid lipase. The released, free cholesterol is then exported from lysosomes for cellular needs or storage. This ... ...

    Abstract Low-density lipoprotein particles are taken up by cells and delivered to the lysosome where their cholesterol esters are cleaved off by acid lipase. The released, free cholesterol is then exported from lysosomes for cellular needs or storage. This article summarizes recent advances in our understanding of the molecular basis of cholesterol export from lysosomes. Cholesterol export requires NPC intracellular cholesterol transporter 1 (NPC1) and NPC2, genetic mutations of which can cause Niemann-Pick type C disease, a disorder characterized by massive lysosomal accumulation of cholesterol and glycosphingolipids. Analysis of the NPC1 and NPC2 structures and biochemical properties, together with new structures of the related Patched (PTCH) protein, provides new clues to the mechanisms by which NPC proteins may function.
    MeSH term(s) Biological Transport ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cholesterol/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; Lysosomes/metabolism ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Mutation ; Niemann-Pick Disease, Type C/physiopathology
    Chemical Substances Carrier Proteins ; Intracellular Signaling Peptides and Proteins ; Membrane Glycoproteins ; NPC1 protein, human ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2019-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.TM118.004165
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.108: Show issues Location:
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  6. Article ; Online: LRRK2 and Rab GTPases.

    Pfeffer, Suzanne R

    Biochemical Society transactions

    2018  Volume 46, Issue 6, Page(s) 1707–1712

    Abstract: Leucine-rich repeat kinase 2 (LRRK2) is mutated in familial Parkinson's disease, and pathogenic mutations activate the kinase activity. A tour de force screen by Mann and Alessi and co-workers identified a subset of Rab GTPases as bona fide LRRK2 ... ...

    Abstract Leucine-rich repeat kinase 2 (LRRK2) is mutated in familial Parkinson's disease, and pathogenic mutations activate the kinase activity. A tour de force screen by Mann and Alessi and co-workers identified a subset of Rab GTPases as bona fide LRRK2 substrates. Rab GTPases are master regulators of membrane trafficking and this short review will summarize what we know about the connection between LRRK2 and this family of regulatory proteins. While, in most cases, Rab GTPase phosphorylation is predicted to interfere with Rab protein function, the discovery of proteins that show preferential binding to phosphorylated Rabs suggests that more complex interactions may also contribute to mutant LRRK2-mediated pathology.
    MeSH term(s) Animals ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Phosphorylation/genetics ; Phosphorylation/physiology ; Protein Transport/genetics ; Protein Transport/physiology ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism
    Chemical Substances Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; rab GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2018-11-22
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 184237-7
    ISSN 1470-8752 ; 0300-5127
    ISSN (online) 1470-8752
    ISSN 0300-5127
    DOI 10.1042/BST20180470
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    Zs.A 944: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  7. Article ; Online: Rab GTPases: master regulators that establish the secretory and endocytic pathways.

    Pfeffer, Suzanne R

    Molecular biology of the cell

    2017  Volume 28, Issue 6, Page(s) 712–715

    Abstract: Several of the most important discoveries in the field of membrane traffic have come from studies of Rab GTPases by Marino Zerial and Peter Novick and their colleagues. Zerial was the first to discover that Rab GTPases represent identity markers for ... ...

    Abstract Several of the most important discoveries in the field of membrane traffic have come from studies of Rab GTPases by Marino Zerial and Peter Novick and their colleagues. Zerial was the first to discover that Rab GTPases represent identity markers for different membrane-bound compartments, and each Rab organizes a collection of specific effectors into function-specifying membrane microdomains to carry out receptor trafficking. Novick discovered that the order (and thus polarity) of Rab GTPases along the secretory and endocytic pathways are established by their specific, cognate guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which partner with one Rab to regulate the subsequent- and prior-acting Rabs. Such so-called Rab cascades have evolved to establish domains that contain unique Rab proteins and their cognate effectors, which drive all steps of membrane trafficking. These findings deserve much broader recognition by the biomedical research community and are highlighted here, along with open questions that require serious attention for full understanding of the molecular basis of Rab GTPase-regulated membrane trafficking in eukaryotic cells.
    MeSH term(s) Animals ; Biological Transport ; Endocytosis/physiology ; Eukaryotic Cells/metabolism ; GTPase-Activating Proteins/metabolism ; Guanine Nucleotide Exchange Factors/metabolism ; Guanine Nucleotide Exchange Factors/physiology ; Humans ; Protein Transport ; Secretory Pathway/physiology ; rab GTP-Binding Proteins/metabolism ; rab GTP-Binding Proteins/physiology
    Chemical Substances GTPase-Activating Proteins ; Guanine Nucleotide Exchange Factors ; rab GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2017-03-15
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E16-10-0737
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2853: Show issues Location:
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    Zs.MO 410: Show issues

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  8. Article ; Online: Clues to NPC1-mediated cholesterol export from lysosomes.

    Pfeffer, Suzanne R

    Proceedings of the National Academy of Sciences of the United States of America

    2016  Volume 113, Issue 29, Page(s) 7941–7943

    MeSH term(s) Biological Transport ; Carrier Proteins ; Cholesterol ; Humans ; Lysosomes ; Membrane Glycoproteins ; Niemann-Pick Diseases ; Proteins
    Chemical Substances Carrier Proteins ; Membrane Glycoproteins ; Proteins ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2016--19
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1608530113
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    Zs.A 1148: Show issues Location:
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  9. Article: Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson's disease.

    Khan, Shahzad S / Jaimon, Ebsy / Lin, Yu-En / Nikoloff, Jonas / Tonelli, Francesca / Alessi, Dario R / Pfeffer, Suzanne R

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Activating LRRK2 mutations cause Parkinson's disease. Previously, we showed that cholinergic interneurons and astrocytes but not medium spiny neurons of the dorsal striatum lose primary cilia in LRRK2 mutant mice. Single nucleus RNA sequencing shows that ...

    Abstract Activating LRRK2 mutations cause Parkinson's disease. Previously, we showed that cholinergic interneurons and astrocytes but not medium spiny neurons of the dorsal striatum lose primary cilia in LRRK2 mutant mice. Single nucleus RNA sequencing shows that cilia loss in cholinergic interneurons correlates with higher LRRK2 expression and decreased glial derived neurotrophic factor transcription. Nevertheless, much higher LRRK2 expression is seen in medium spiny neurons that have normal cilia in mice and humans. In parallel with decreased striatal dopaminergic neurite density, LRRK2 G2019S neurons show increased autism-linked CNTN5 adhesion protein expression; glial cells show significant loss of ferritin heavy chain. Human striatal tissue from LRRK2 pathway mutation carriers and idiopathic Parkinson's disease show similar cilia loss in cholinergic interneurons and astrocytes and overall loss of such neurons. These data strongly suggest that loss of cilia in specific striatal cell types decreases neuroprotection for dopamine neurons in mice and human Parkinson's disease.
    Language English
    Publishing date 2024-01-16
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.01.15.575737
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Lipoprotein secretion: It takes two to TANGO.

    Pfeffer, Suzanne R

    The Journal of cell biology

    2016  Volume 213, Issue 3, Page(s) 297–299

    Abstract: An unsolved mystery in cell biology is how unusually large secretory cargoes are exported from the endoplasmic reticulum. In this issue, Santos et al. (2016. J. Cell Biol http://dx.doi.org/10.1083/jcb.201603072) report the function of a Mia2/cTAGE5 ... ...

    Abstract An unsolved mystery in cell biology is how unusually large secretory cargoes are exported from the endoplasmic reticulum. In this issue, Santos et al. (2016. J. Cell Biol http://dx.doi.org/10.1083/jcb.201603072) report the function of a Mia2/cTAGE5 transcript fusion, named TALI, in the endoplasmic reticulum export of chylomicrons and very low-density lipoproteins, but not collagen XII.
    MeSH term(s) Animals ; Collagen ; Endoplasmic Reticulum ; Lipoproteins, LDL
    Chemical Substances Lipoproteins, LDL ; Collagen (9007-34-5)
    Language English
    Publishing date 2016-05-02
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.201604084
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