title: Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia.
abstract: Hereditary spastic paraplegias are a group of inherited motor neuron diseases characterized by progressive paraparesis and spasticity. Mutations in the spastic paraplegia gene SPG11, encoding spatacsin, cause an autosomal-recessive disease trait; however, the precise knowledge about the role of spatacsin in neurons is very limited. We for the first time analyzed the expression and function of spatacsin in human forebrain neurons derived from human pluripotent stem cells including lines from two SPG11 patients and two controls. SPG11 patients'-derived neurons exhibited downregulation of specific axonal-related genes, decreased neurite complexity and accumulation of membranous bodies within axonal processes. Altogether, these data point towards axonal pathologies in human neurons with SPG11 mutations. To further corroborate spatacsin function, we investigated human pluripotent stem cell-derived neurons and mouse cortical neurons. In these cells, spatacsin was located in axons and dendrites. It colocalized with cytoskeletal and synaptic vesicle (SV) markers and was present in synaptosomes. Knockdown of spatacsin in mouse cortical neurons evidenced that the loss of function of spatacsin leads to axonal instability by downregulation of acetylated tubulin. Finally, time-lapse assays performed in SPG11 patients'-derived neurons and spatacsin-silenced mouse neurons highlighted a reduction in the anterograde vesicle trafficking indicative of impaired axonal transport. By employing SPG11 patient-derived forebrain neurons and mouse cortical neurons, this study provides the first evidence that SPG11 is implicated in axonal maintenance and cargo trafficking. Understanding the cellular functions of spatacsin will allow deciphering mechanisms of motor cortex dysfunction in autosomal-recessive hereditary spastic paraplegia.
authors.affiliation: IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Glueckstrasse 6, Erlangen 91054, Germany.
authors.forename: Francesc
authors.initials: F
authors.lastname: Pérez-Brangulí
authors.affiliation: IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Glueckstrasse 6, Erlangen 91054, Germany.
authors.forename: Himanshu K
authors.initials: HK
authors.lastname: Mishra
authors.affiliation: IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Glueckstrasse 6, Erlangen 91054, Germany.
authors.forename: Iryna
authors.initials: I
authors.lastname: Prots
authors.affiliation: IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Glueckstrasse 6, Erlangen 91054, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Havlicek
authors.affiliation: Department of Molecular Neurology.
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Kohl
authors.affiliation: IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Glueckstrasse 6, Erlangen 91054, Germany.
authors.forename: Domenica
authors.initials: D
authors.lastname: Saul
authors.affiliation: IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Glueckstrasse 6, Erlangen 91054, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Rummel
authors.affiliation: Department of Pathology and Experimental Therapeutics, Universitat de Barcelona (UB)-Campus Bellvitge, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Dorca-Arevalo
authors.affiliation: IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Glueckstrasse 6, Erlangen 91054, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Regensburger
authors.affiliation: IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Glueckstrasse 6, Erlangen 91054, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Graef
authors.affiliation: Institute of Biochemistry Emil-Fischer Zentrum, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Fahrstrasse 17, Erlangen 91054, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sock
authors.affiliation: Department of Pathology and Experimental Therapeutics, Universitat de Barcelona (UB)-Campus Bellvitge, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Blasi
authors.affiliation: Department of Psychiatry and.
authors.forename: Teja W
authors.initials: TW
authors.lastname: Groemer
authors.affiliation: Department of Ophthalmology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Schwabachanlage 6, Erlangen 91054, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.affiliation: Department of Molecular Neurology.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.affiliation: IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Glueckstrasse 6, Erlangen 91054, Germany beate.winner@med.uni-erlangen.de.
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000473:pathology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D011506:Proteins; C520412:SPG11 protein, human; C000597153:SPG11 protein, mouse; D014404:Tubulin