title: Motor neuron-specific disruption of proteasomes, but not autophagy, replicates amyotrophic lateral sclerosis.
abstract: Evidence suggests that protein misfolding is crucially involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, controversy still exists regarding the involvement of proteasomes or autophagy in ALS due to previous conflicting results. Here, we show that impairment of the ubiquitin-proteasome system, but not the autophagy-lysosome system in motor neurons replicates ALS in mice. Conditional knock-out mice of the proteasome subunit Rpt3 in a motor neuron-specific manner (Rpt3-CKO) showed locomotor dysfunction accompanied by progressive motor neuron loss and gliosis. Moreover, diverse ALS-linked proteins, including TAR DNA-binding protein 43 kDa (TDP-43), fused in sarcoma (FUS), ubiquilin 2, and optineurin were mislocalized or accumulated in motor neurons, together with other typical ALS hallmarks such as basophilic inclusion bodies. On the other hand, motor neuron-specific knock-out of Atg7, a crucial component for the induction of autophagy (Atg7-CKO), only resulted in cytosolic accumulation of ubiquitin and p62, and no TDP-43 or FUS pathologies or motor dysfunction was observed. These results strongly suggest that proteasomes, but not autophagy, fundamentally govern the development of ALS in which TDP-43 and FUS proteinopathy may play a crucial role. Enhancement of proteasome activity may be a promising strategy for the treatment of ALS.
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tashiro
authors.forename: Makoto
authors.initials: M
authors.lastname: Urushitani
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Inoue
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Maya
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.forename: Hidemi
authors.initials: H
authors.lastname: Misawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D001343:Autophagy; D001522:Behavior, Animal; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D026901:Membrane Transport Proteins; C501288:Optn protein, mouse; D021122:Protein Subunits; D034702:RNA-Binding Protein FUS; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex