Golgi fragmentation is a common feature in multiple neurodegenerative diseases; however, the precise mechanism that causes fragmentation remains obscure. A potential link between Cdk5 and Golgi fragmentation in Alzheimer's disease (AD) was investigated in this study. Because Golgi is physiologically fragmented during mitosis by Cdc2 kinase and current Cdk5-specific chemical inhibitors target Cdc2 as well, development of novel tools to modulate Cdk5 activity was essential. These enzyme modulators, created by fusing TAT sequence to Cdk5 activators and an inhibitor peptide, enable specific activation and inhibition of Cdk5 activity with high temporal control. These genetic tools revealed a major role of Cdk5 in Golgi fragmentation upon beta-amyloid and glutamate stimulation in differentiated neuronal cells and primary neurons. A crucial role of Cdk5 was further confirmed when Cdk5 activation alone resulted in robust Golgi disassembly. The underlying mechanism was unraveled using a chemical genetic screen, which yielded cis-Golgi matrix protein GM130 as a novel substrate of Cdk5. Identification of the Cdk5 phosphorylation site on GM130 suggested a mechanism by which Cdk5 may cause Golgi fragmentation upon deregulation in AD. As Cdk5 is activated in several neurodegenerative diseases where Golgi disassembly also occurs, this may be a common mechanism among multiple disorders.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441653 | PMC |
| http://dx.doi.org/10.1091/mbc.e07-11-1106 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Inhibition of mitochondrial energy production leads to reorganization of the plant endomembrane system.
Plant Physiol
January 2025
State Key Laboratory of Microbial Metabolism & Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China, P. R.
Mitochondria have generated the bulk of ATP to fuel cellular activities, including membrane trafficking, since the beginning of eukaryogenesis. How inhibition of mitochondrial energy production will affect the form and function of the endomembrane system and whether such changes are specific in today's cells remain unclear. Here, we treated Arabidopsis thaliana with antimycin A (AA), a potent inhibitor of the mitochondrial electron transport chain (mETC), as well as other mETC inhibitors and an uncoupler.
View Article and Find Full Text PDFCoordination Chemistry of Mixed-Donor Pyridine-Containing Macrocyclic Ligands: From Optical to Redox Chemosensors for Heavy Metal Ions.
Molecules
December 2024
Centre for Research University Services (CeSAR), Università degli Studi di Cagliari, S.S. 554 Bivio per Sestu, 09042 Monserrato, Italy.
2,8-Dithia-5-aza-2,6-pyridinophane () has been used as a receptor unit in the construction of the conjugated redox chemosensor 5-ferrocenylmethyl-2,8-dithia-5-aza-2,6-pyridinophane (). In order to further explore the coordination chemistry of , and comparatively, that of its structural analogue 2,11-dithia-5,8-diaza-2,6-pyridinophane (), featuring two secondary nitrogen atoms in the macrocyclic unit, the crystal structures of the new synthesised complexes [Pb()(ClO)]·½CHCN, [Cu()](ClO)·CHCN and [Cd()(NO)]NO were determined by X-ray diffraction analysis. The electrochemical response of towards the metal ions Cu, Zn, Cd, Hg, and Pb was investigated by cyclic voltammetry (CV) in CHCl/CHCN 0.
View Article and Find Full Text PDFSLC10A7 regulates O-GalNAc glycosylation and Ca homeostasis in the secretory pathway: insights into SLC10A7-CDG.
Cell Mol Life Sci
January 2025
Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale Et Fonctionnelle, 59000, Lille, France.
Glycans are known to be fundamental for many cellular and physiological functions. Congenital disorders of glycosylation (CDG) currently encompassing over 160 subtypes, are characterized by glycan synthesis and/or processing defects. Despite the increasing number of CDG patients, therapeutic options remain very limited as our knowledge on glycan synthesis is fragmented.
View Article and Find Full Text PDFAge-associated interplay between zinc deficiency and Golgi stress hinders microtubule-dependent cellular signaling and epigenetic control.
Dev Cell
December 2024
Department of Biological Sciences, Ajou University, Suwon 16499, South Korea. Electronic address:
Golgi abnormalities have been linked to aging and age-related diseases, yet the underlying causes and functional consequences remain poorly understood. This study identifies the interaction between age-associated zinc deficiency and Golgi stress as a critical factor in cellular aging. Senescent Golgi bodies from human fibroblasts show a fragmented Golgi structure, associated with a decreased interaction of the zinc-dependent Golgi-stacking protein complex Golgin45-GRASP55.
View Article and Find Full Text PDFSARS-CoV-2 membrane protein induces neurodegeneration via affecting Golgi-mitochondria interaction.
Transl Neurodegener
December 2024
Department of Neurosciences, Hengyang Medical School, University of South China, Hengyang, 421009, China.
Background: Neurological complications are a significant concern of Coronavirus Disease 2019 (COVID-19). However, the pathogenic mechanism of neurological symptoms associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is poorly understood.
Methods: We used Drosophila as a model to systematically analyze SARS-CoV-2 genes encoding structural and accessory proteins and identified the membrane protein (M) that disrupted mitochondrial functions in vivo.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!