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Cao M.,Howard Hughes Medical Institute | Milosevic I.,Howard Hughes Medical Institute | Milosevic I.,European Neuroscience Institute ENI | Giovedi S.,Howard Hughes Medical Institute | And 2 more authors.
Journal of Neuroscience | Year: 2014

Several proteins encoded by PD genes are implicated in synaptic vesicle traffic. Endophilin, a key factor in the endocytosis of synaptic vesicles, was shown to bind to, and be ubiquitinated by, the PD-linked E3 ubiquitin ligase Parkin. Here we report that Parkin’s level is specifically upregulated in brain and fibroblasts of endophilin mutant mice due to increased transcriptional regulation. Studies of transfected HEK293T cells show that Parkin ubiquitinates not only endophilin, but also its major binding partners, dynamin and synaptojanin 1. These results converge with the recently reported functional relationship of endophilin to the PD gene LRRK2 and with the identification of a PD-linked synaptojanin 1 mutation, in providing evidence for a link between PD and endocytosis genes. ©2014 the authors.


Sugie A.,German Center for Neurodegenerative Diseases | Hakeda-Suzuki S.,Tokyo Institute of Technology | Silies M.,European Neuroscience Institute ENI | Shimozono M.,Tokyo Institute of Technology | And 3 more authors.
Neuron | Year: 2015

Neural activity contributes to the regulation of the properties of synapses in sensory systems, allowing for adjustment to a changing environment. Little is known about how synaptic molecular components are regulated to achieve activity-dependent plasticity at central synapses. Here, we found that after prolonged exposure to natural ambient light the presynaptic active zone in Drosophila photoreceptors undergoes reversible remodeling, including loss of Bruchpilot, DLiprin-α, and DRBP, but not of DSyd-1 or Cacophony. The level of depolarization of the postsynaptic neurons is critical for the light-induced changes in active zone composition in thephotoreceptors, indicating the existence of a feedback signal. In search of this signal, we have identified a crucial role of microtubule meshwork organization downstream of the divergent canonical Wnt pathway, potentially via Kinesin-3 Imac. These data reveal that active zone composition can be regulated invivo and identify the underlying molecular machinery. Sugie etal. show that presynaptic active zones can undergo molecular remodeling invivo. Activation of postsynaptic neurons feeds back to control Drosophila photoreceptor active zone composition via the divergent canonical Wnt pathway and the regulation of microtubule stability. © 2015 Elsevier Inc.


Hannemann M.,European Neuroscience Institute ENI | Hannemann M.,International Max Planck Research School Molecular Biology | Sasidharan N.,European Neuroscience Institute ENI | Sasidharan N.,International Max Planck Research School Neuroscience | And 10 more authors.
PLoS Genetics | Year: 2012

Dense core vesicles (DCVs) are thought to be generated at the late Golgi apparatus as immature DCVs, which subsequently undergo a maturation process through clathrin-mediated membrane remodeling events. This maturation process is required for efficient processing of neuropeptides within DCVs and for removal of factors that would otherwise interfere with DCV release. Previously, we have shown that the GTPase, RAB-2, and its effector, RIC-19, are involved in DCV maturation in Caenorhabditis elegans motoneurons. In rab-2 mutants, specific cargo is lost from maturing DCVs and missorted into the endosomal/lysosomal degradation route. Cargo loss could be prevented by blocking endosomal delivery. This suggests that RAB-2 is involved in retention of DCV components during the sorting process at the Golgi-endosomal interface. To understand how RAB-2 activity is regulated at the Golgi, we screened for RAB-2-specific GTPase activating proteins (GAPs). We identified a potential RAB-2 GAP, TBC-8, which is exclusively expressed in neurons and which, when depleted, shows similar DCV maturation defects as rab-2 mutants. We could demonstrate that RAB-2 binds to its putative GAP, TBC-8. Interestingly, TBC-8 also binds to the RAB-2 effector, RIC-19. This interaction appears to be conserved as TBC-8 also interacted with the human ortholog of RIC-19, ICA69. Therefore, we propose that a dynamic ON/OFF cycling of RAB-2 at the Golgi induced by the GAP/effector complex is required for proper DCV maturation. © 2012 Hannemann et al.


Benito E.,German Center for Neurodegenerative Diseases | Urbanke H.,German Center for Neurodegenerative Diseases | Ramachandran B.,European Neuroscience Institute ENI | Barth J.,German Center for Neurodegenerative Diseases | And 15 more authors.
Journal of Clinical Investigation | Year: 2015

Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's disease (AD). Effective therapies for these diseases are lacking. Here, we evaluated mouse models of age-Associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity in the brain and peripheral organs. We determined that aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region as the result of epigenetic-dependent alterations in gene expression. In both amyloid and aging models, inflammation was associated with increased gene expression linked to a subset of transcription factors, while plasticity gene deregulation was differentially mediated. Amyloid pathology impaired histone acetylation and decreased expression of plasticity genes, while aging altered H4K12 acetylation-linked differential splicing at the intron-exon junction in neurons, but not nonneuronal cells. Furthermore, oral administration of the clinically approved histone deacetylase inhibitor vorinostat not only restored spatial memory, but also exerted antiinflammatory action and reinstated epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This study provides a systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and suggests that histone deacetylase inhibitors should be further explored as a cost-effective therapeutic strategy against age-Associated cognitive decline.


Kuczera T.,University of Gottingen | Kuczera T.,European Neuroscience Institute ENI | Bayram O.,University of Gottingen | Sari F.,University of Gottingen | And 3 more authors.
Cell Cycle | Year: 2010

Progression through mitosis requires the activity of cyclin-dependent kinases (CDKs) associated with regulatory cyclin subunits. In the yeast Saccharomyces cerevisiae, Clb2 has the most important role among the four mitotic cyclins, Clb1-4, manifested by data showing that simultaneous deletion of the CLB1, CLB3 and CLB4 genes has only minor effects on mitosis. Thus, Clb2 alone is sufficient for all essential CDK functions in mitosis, such as the assembly of bipolar spindles and spindle elongation. Here, we show that a modification of Clb2, by the C-terminal addition of a Myc12 epitope, causes the loss of one specific mitotic function of Clb2. Strains carrying CLB2-MYC12 are nonviable in the absence of the CLB3 and CLB4 genes, because the modified Clb2 version fails to promote assembly of the mitotic spindle. In contrast, Clb2-Myc12 has no apparent defects in late mitotic functions and, furthermore, induces the switch from polarized to isotropic growth with similar efficiency as the endogenous Clb2. Thus, the presence of the Myc12 epitope selectively inactivates Clb2's capacity to promote spindle formation. Clb2-Myc12 represents therefore the first version of Clb2 impaired in one specific mitotic function. We conclude that the major mitotic functions of this cyclin can be unequivocally dissected. © 2010 Landes Bioscience.

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