title: Molecular chaperone mediated late-stage neuroprotection in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in superoxide dismutase (SOD1) are associated with familial ALS and lead to SOD1 protein misfolding and aggregation. Here we show that the molecular chaperone, HSJ1 (DNAJB2), mutations in which cause distal hereditary motor neuropathy, can reduce mutant SOD1 aggregation and improve motor neuron survival in mutant SOD1 models of ALS. Overexpression of human HSJ1a (hHSJ1a) in vivo in motor neurons of SOD1(G93A) transgenic mice ameliorated disease. In particular, there was a significant improvement in muscle force, increased motor unit number and enhanced motor neuron survival. hHSJ1a was present in a complex with SOD1(G93A) and led to reduced SOD1 aggregation at late stages of disease progression. We also observed altered ubiquitin immunoreactivity in the double transgenic animals, suggesting that ubiquitin modification might be important for the observed improvements. In a cell model of SOD1(G93A) aggregation, HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1 aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner. Collectively, the data suggest that HSJ1a acts on mutant SOD1 through a combination of chaperone, co-chaperone and pro-ubiquitylation activity. These results show that targeting SOD1 protein misfolding and aggregation in vivo can be neuroprotective and suggest that manipulation of DnaJ molecular chaperones might be useful in the treatment of ALS.
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Novoselov
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Mustill
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gray
authors.forename: James R
authors.initials: JR
authors.lastname: Dick
authors.forename: Naheed
authors.initials: N
authors.lastname: Kanuga
authors.forename: Bernadett
authors.initials: B
authors.lastname: Kalmar
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001835:Body Weight; D002417:Cattle; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008136:Longevity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D009046:Motor Neurons / Q000473:pathology; D009132:Muscles / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D009929:Organ Size; D020836:Protein Structure, Quaternary; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C121958:DNAJB2 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D018696:Neuroprotective Agents; D013482:Superoxide Dismutase
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