title: ZFYVE26/SPASTIZIN: a close link between complicated hereditary spastic paraparesis and autophagy.
abstract: Defective autophagy is associated with neurodegenerative disorders including Alzheimer, Parkinson and Huntington diseases, amyotrophic lateral sclerosis and SCA (spinocerebellar ataxias). Autophagy defects were detected also in SPG49, a complicated form of hereditary spastic paraparesis (cHSP) associated with mutations in the TECPR2 gene, suggesting a role of autophagy also in this heterogeneous group of neurodegenerative diseases. We recently found defective autophagy in SPG15, another HSP subtype associated with mutations in the ZFYVE26/SPG15 gene. Patient-derived cells (fibroblasts/lymphoblasts) carrying different ZFYVE26 mutations show accumulation of immature autophagosomes and increased MAP1LC3B-II and SQSTM1/p62 levels. These findings indicate that ZFYVE26 is a key determinant of autophagosome maturation, which is impaired when the protein is defective or absent. Replication of these findings in primary neurons supports the relevance of defective autophagy in SPG15-related neurodegeneration.
authors.affiliation: Scientific Institute IRCCS E. Medea; Laboratory of Molecular Biology; Lecco, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Vantaggiato
authors.affiliation: Unit of Clinical Pharmacology; Department of Biomedical and Clinical Sciences; University Hospital "Luigi Sacco"; Università di Milano; Milan, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.affiliation: Scientific Institute IRCCS E. Medea; Laboratory of Molecular Biology; Lecco, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bassi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D020336:Paraparesis, Spastic / Q000235:genetics*; D010588:Phagosomes / Q000378:metabolism; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C528699:ZFYVE26 protein, human
keywords: BECN1/Beclin 1; SPG15; ZFYVE26/SPASTIZIN; autophagosome maturation; autophagy; complicated hereditary spastic paraparesis