title: Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15.
abstract: Hereditary spastic paraparesis type 15 is a recessive complicated form of the disease clinically characterized by slowly progressive spastic paraparesis and mental deterioration with onset between the first and second decade of life. Thinning of corpus callosum is the neuroradiological distinctive sign frequently associated with white matter abnormalities. The causative gene, ZFYVE26, encodes a large protein of 2539 amino acid residues, termed spastizin, containing three recognizable domains: a zinc finger, a leucine zipper and a FYVE domain. Spastizin protein has a diffuse cytoplasmic distribution and co-localizes partially with early endosomes, the endoplasmic reticulum, microtubules and vesicles involved in protein trafficking. In addition, spastizin localizes to the mid-body during the final step of mitosis and contributes to successful cytokinesis. Spastizin interacts with Beclin 1, a protein required for cytokinesis and autophagy, which is the major lysosome-mediated degradation process in the cell. In view of the Beclin 1-spastizin interaction, we investigated the possible role of spastizin in autophagy. We carried out this analysis by using lymphoblast and fibroblast cells derived from four different spastizin mutated patients (p.I508N, p.L243P, p.R1209fsX, p.S1312X) and from control subjects. Of note, the truncating p.R1209fsX and p.S1312X mutations lead to loss of spastizin protein. The results obtained indicate that spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation. In cells lacking spastizin or with mutated forms of the protein, spastizin interaction with Beclin 1 is lost although the formation of the Beclin 1-UVRAG-Rubicon complex can still be observed. However, in these cells we demonstrate an impairment of autophagosome maturation and an accumulation of immature autophagosomes. Autophagy defects with autophagosome accumulation can be observed also in neuronal cells upon spastizin silencing. These results indicate that autophagy is a central process in the pathogenesis of complicated forms of hereditary spastic paraparesis with thin corpus callosum.
authors.affiliation: 1 Scientific Institute IRCCS E. Medea, Laboratory of Molecular Biology, 23842 Bosisio Parini, Lecco, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Vantaggiato
authors.forename: Claudia
authors.initials: C
authors.lastname: Crimella
authors.forename: Giovanni
authors.initials: G
authors.lastname: Airoldi
authors.forename: Roman
authors.initials: R
authors.lastname: Polishchuk
authors.forename: Sara
authors.initials: S
authors.lastname: Bonato
authors.forename: Erika
authors.initials: E
authors.lastname: Brighina
authors.forename: Marina
authors.initials: M
authors.lastname: Scarlato
authors.forename: Olimpia
authors.initials: O
authors.lastname: Musumeci
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Filippo Maria
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bassi
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D002352:Carrier Proteins / Q000235:genetics*; D003337:Corpus Callosum / Q000473:pathology; D011992:Endosomes / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D002352:Carrier Proteins; D008565:Membrane Proteins; C528699:ZFYVE26 protein, human
keywords: Beclin 1; SPG15; autophagosome maturation; autophagy; spastizin
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