Autophagic dysfunction: a clue in neurodegenerative diseases and lysosomal storage disorders (Abstract/Poster in convegno)

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  • Autophagic dysfunction: a clue in neurodegenerative diseases and lysosomal storage disorders (Abstract/Poster in convegno) (literal)
Anno
  • 2014-01-01T00:00:00+01:00 (literal)
Alternative label
  • Galizzi G, Deidda I, Russo D, Cascio C, Guarneri P. (2014)
    Autophagic dysfunction: a clue in neurodegenerative diseases and lysosomal storage disorders
    in Convegno monotematico SIF - LOOKING INSIDE NEURONS FOR A BETTER PHARMACOLOGICAL INTERVENTION: THE CONTRIBUTION OF IMAGING TO THE STUDY OF NEURODEGENERATIVE DISEASES, Catania, 20 /06/2014
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Galizzi G, Deidda I, Russo D, Cascio C, Guarneri P. (literal)
Note
  • Poster (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • CNR Institute of Biomedicine and Molecular Immunology, Palermo, Italy (literal)
Titolo
  • Autophagic dysfunction: a clue in neurodegenerative diseases and lysosomal storage disorders (literal)
Abstract
  • The importance of aggregated proteins and of autophagosome/lysosomal dysfunction in the pathogenesis of neurodegenerative diseases has been extensively discussed in these last years. Emerging studies point to several promising experimental pro-autophagy drugs that decrease levels of toxic aggregates, being so beneficial in the context of aging and various neurodegenerative diseases' models. However, because the intrinsic nature of autophagy and its interconnection with several cellular homeostatic mechanisms, caution should be exercised with respect to autophagy modulating drugs; extensive autophagy actually results in the killing of cells. Autophagy (referring to macroautophagy herein) is indeed a multi-step process, still under investigation. Definition of autophagy stages and progress in tissues/cells is important for targeting its dysfunction towards its prevention in diseases. Analyses by electron-microscopy and immunohisto/cytochemistry along with biochemical analyses allow to investigate autophagosomes at different maturation stages, and to distinguish whether autophagosome accumulation results from increased autophagic initiation or decreased autophagic completion. We recently demonstrated that CLN8 protein, an ER-resident protein, interacts with GATE-16, an Atg8 ortholog that participates with LC3 to autophagosome biogenesis, and with BNIP3 and BNIP3L/NIX, selective autophagy receptors for the clearance of mitochondria (mitophagy). Mutations in CLN8 gene are causative of two variants of neuronal ceroid lipofuscinoses (NCLs), autosomal inherited neurodegenerative diseases classified as lysosomal storage disorders. NCLs manifest in early childhood, rarely in adults, and with symptoms of progressive cognitive and motor deterioration, loss of vision and epilepsy. They are linked to distinct mutant proteins but all involved in the endolysosomal/pathway and ultimately leading to lysosomal autofluorescent accumulation of ceroid, lipofuscin and proteins. Using a CLN8-mutant mouse model, we show a stepwise biochemical and in situ characterization of autophagy/mitophagy dysfunction in CNS structures affected by the disease, suggesting that defects in sealing rather than in induction of autophagosome formation is responsible for onset and progression of CLN8-NCL disease (literal)
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