title: Silencing of the Drosophila ortholog of SOX5 leads to abnormal neuronal development and behavioral impairment.
abstract: SOX5 encodes a transcription factor that is expressed in multiple tissues including heart, lung and brain. Mutations in SOX5 have been previously found in patients with amyotrophic lateral sclerosis (ALS) and developmental delay, intellectual disability and dysmorphic features. To characterize the neuronal role of SOX5, we silenced the Drosophila ortholog of SOX5, Sox102F, by RNAi in various neuronal subtypes in Drosophila. Silencing of Sox102F led to misorientated and disorganized michrochaetes, neurons with shorter dendritic arborization (DA) and reduced complexity, diminished larval peristaltic contractions, loss of neuromuscular junction bouton structures, impaired olfactory perception, and severe neurodegeneration in brain. Silencing of SOX5 in human SH-SY5Y neuroblastoma cells resulted in a significant repression of WNT signaling activity and altered expression of WNT-related genes. Genetic association and meta-analyses of the results in several large family-based and case-control late-onset familial Alzheimer's disease (LOAD) samples of SOX5 variants revealed several variants that show significant association with AD disease status. In addition, analysis for rare and highly penetrate functional variants revealed four novel variants/mutations in SOX5, which taken together with functional prediction analysis, suggests a strong role of SOX5 causing AD in the carrier families. Collectively, these findings indicate that SOX5 is a novel candidate gene for LOAD with an important role in neuronal function. The genetic findings warrant further studies to identify and characterize SOX5 variants that confer risk for AD, ALS and intellectual disability.
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Diseases, Charlestown, MA 02129, USA.
authors.forename: Airong
authors.initials: A
authors.lastname: Li
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Diseases, Charlestown, MA 02129, USA.
authors.forename: Basavaraj
authors.initials: B
authors.lastname: Hooli
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Diseases, Charlestown, MA 02129, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Mullin
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Diseases, Charlestown, MA 02129, USA.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Tate
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Diseases, Charlestown, MA 02129, USA.
authors.forename: Adele
authors.initials: A
authors.lastname: Bubnys
authors.affiliation: Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Rory
authors.initials: R
authors.lastname: Kirchner
authors.affiliation: Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Chapman
authors.affiliation: Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.|Center for Cancer Research, University of Melbourne, Melbourne 3000, Australia and.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hofmann
authors.affiliation: Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.|Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
authors.forename: Winston
authors.initials: W
authors.lastname: Hide
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Diseases, Charlestown, MA 02129, USA.
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics*; D020868:Gene Silencing; D056726:Genetic Association Studies; D006801:Humans; D009469:Neuromuscular Junction / Q000235:genetics / Q000473:pathology; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D055755:SOXD Transcription Factors / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; C587040:SOX102F protein, Drosophila; C490301:SOX5 protein, human; D055755:SOXD Transcription Factors