title: Sacs knockout mice present pathophysiological defects underlying autosomal recessive spastic ataxia of Charlevoix-Saguenay.
abstract: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS [MIM 270550]) is an early-onset neurodegenerative disorder caused by mutations in the SACS gene. Over 170 SACS mutations have been reported worldwide and are thought to cause loss of function of sacsin, a poorly characterized and massive 520 kDa protein. To establish an animal model and to examine the pathophysiological basis of ARSACS, we generated Sacs knockout (Sacs(-/-)) mice. Null animals displayed an abnormal gait with progressive motor, cerebellar and peripheral nerve dysfunctions highly reminiscent of ARSACS. These clinical features were accompanied by an early onset, progressive loss of cerebellar Purkinje cells followed by spinal motor neuron loss and peripheral neuropathy. Importantly, loss of sacsin function resulted in abnormal accumulation of non-phosphorylated neurofilament (NF) bundles in the somatodendritic regions of vulnerable neuronal populations, a phenotype also observed in an ARSACS brain. Moreover, motor neurons cultured from Sacs(-/-) embryos exhibited a similar NF rearrangement with significant reduction in mitochondrial motility and elongated mitochondria. The data points to alterations in the NF cytoskeleton and defects in mitochondrial dynamics as the underlying pathophysiological basis of ARSACS.
authors.affiliation: Department of Neurology and Neurosurgery, Laboratory of Neurogenetics of Motion and.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Larivière
authors.affiliation: Department of Neurology and Neurosurgery, Laboratory of Neurogenetics of Motion and.
authors.forename: Rébecca
authors.initials: R
authors.lastname: Gaudet
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4.
authors.forename: Benoit J
authors.initials: BJ
authors.lastname: Gentil
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4.
authors.forename: Martine
authors.initials: M
authors.lastname: Girard
authors.affiliation: Department of Neurology and Neurosurgery, Laboratory of Neurogenetics of Motion and.
authors.forename: Talita Cristiane
authors.initials: TC
authors.lastname: Conte
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4.
authors.forename: Sandra
authors.initials: S
authors.lastname: Minotti
authors.affiliation: Department of Neurology and Neurosurgery, Laboratory of Neurogenetics of Motion and.
authors.forename: Kim
authors.initials: K
authors.lastname: Leclerc-Desaulniers
authors.affiliation: Groupe de Recherche Axé sur la Structure des Protéines, Department of Biochemistry and.
authors.forename: Kalle
authors.initials: K
authors.lastname: Gehring
authors.affiliation: Department of Pharmacology, McGill University, Montreal, QC, Canada H3G 0B1.
authors.forename: R Anne
authors.initials: RA
authors.lastname: McKinney
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4.
authors.forename: Peter S
authors.initials: PS
authors.lastname: McPherson
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4.
authors.forename: Heather D
authors.initials: HD
authors.lastname: Durham
authors.affiliation: Department of Neurology and Neurosurgery, Laboratory of Neurogenetics of Motion and bernard.brais@mcgill.ca.
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007382:Intermediate Filaments / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology*; D009046:Motor Neurons / Q000166:cytology / Q000473:pathology*; D009128:Muscle Spasticity / Q000235:genetics / Q000503:physiopathology*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology*; D011712:Pyramidal Tracts / Q000473:pathology; D013131:Spine / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology; D046509:Tissue Culture Techniques
chemical_list: D006360:Heat-Shock Proteins; C498616:Sacs protein, mouse