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Retromer Dysfunction and Neurodegenerative Disease.

ABSTRACT: In recent years, genomic, animal and cell biology studies have implicated deficiencies in retromer-mediated trafficking of proteins in an increasing number of neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's Disease (PD) and Frontotemporal Lobar Degener-ation (FTLD). The retromer complex, which is highly conserved across all eukaryotes, regulates the sorting of transmembrane proteins out of endo-somes to the cell surface or to the trans-Golgi network. Within retromer, cargo selection and binding are performed by a trimer of the Vps26, Vps29 and Vps35 proteins, named the "Cargo-Selective Complex (CSC)". Sorting of cargo into tubules for distribution to the trans-Golgi network or the cell sur-face is achieved through the dimeric sorting nexin (SNX) component of retromer and accessory proteins such as the WASH complex which medi-ates the formation of discrete endosomal tubules enabling the sorting of cargo into distinct pathways through production of filamentous actin patch-es. In the present article, we review the molecular structure and function of the retromer and summarize the evidence linking retromer dysfunction to neurodegenerative disease.

SUBMITTER: Reitz C

PROVIDER: S-EPMC5930449 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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Retromer Dysfunction and Neurodegenerative Disease.

Reitz Christiane C

Current genomics 20180501 4

In recent years, genomic, animal and cell biology studies have implicated deficiencies in retromer-mediated trafficking of proteins in an increasing number of neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's Disease (PD) and Frontotemporal Lobar Degener-ation (FTLD). The retromer complex, which is highly conserved across all eukaryotes, regulates the sorting of transmembrane proteins out of endo-somes to the cell surface or to the trans-Golgi network. Within retromer, c ...[more]

PMID: 29755290

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Project description:Mitochondria are the repository for various metabolites involved in diverse energy-generating processes, like the TCA cycle, oxidative phosphorylation, and metabolism of amino acids, fatty acids, and nucleotides, which rely significantly on flavoenzymes, such as oxidases, reductases, and dehydrogenases. Flavoenzymes are functionally dependent on biologically active flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN), which are derived from the dietary component riboflavin, a water soluble vitamin. Riboflavin regulates the structure and function of flavoenzymes through its cofactors FMN and FAD and, thus, protects the cells from oxidative stress and apoptosis. Hence, it is not surprising that any disturbance in riboflavin metabolism and absorption of this vitamin may have consequences on cellular FAD and FMN levels, resulting in mitochondrial dysfunction by reduced energy levels, leading to riboflavin associated disorders, like cataracts, neurodegenerative and cardiovascular diseases, etc. Furthermore, mutations in either nuclear or mitochondrial DNA encoding for flavoenzymes and flavin transporters significantly contribute to the development of various neurological disorders. Moreover, recent studies have evidenced that riboflavin supplementation remarkably improved the clinical symptoms, as well as the biochemical abnormalities, in patients with neuronopathies, like Brown-Vialetto-Van-Laere syndrome (BVVLS) and Fazio-Londe disease. This review presents an updated outlook on the cellular and molecular mechanisms of neurodegenerative disorders in which riboflavin deficiency leads to dysfunction in mitochondrial energy metabolism, and also highlights the significance of riboflavin supplementation in aforementioned disease conditions. Thus, the outcome of this critical assessment may exemplify a new avenue to enhance the understanding of possible mechanisms in the progression of neurodegenerative diseases and may provide new rational approaches of disease surveillance and treatment.

Dataset Information

Retromer Dysfunction and Neurodegenerative Disease.

Publications

Retromer Dysfunction and Neurodegenerative Disease.

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