Grant-in-Aid for Scientific Research (B)
ALS is a fatal neurodegenerative disorder characterized by a selective loss of motor neurons. Multiple toxicity pathways, such as oxidative stress and misfolded protein accumulation, are implicated in the pathogenesis of ALS. We generated SOD1H46R mice either on a Nfe2l2-KO, Sqstm1-KO, or Sqstm1/Als2-double KO background. Loss of SQSTM1 but not NFE2L2 exacerbated disease symptoms. A simultaneous inactivation of SQSTM1 and ALS2 further accelerated the onset of disease. Absence of SQSTM1 accelerated motor neuron degeneration with accompanying the preferential accumulation of ubiquitin-positive aggregates in spinal neurons. Surprisingly, loss of SQSTM1 rather suppressed the accumulation of insoluble polyubiquitinated proteins, suggesting that the selective accumulation of aggregates in neurons might be more insulting than the insoluble proteins. Collectively, SQSTM1 and ALS2 have distinct but additive protective roles against mutant SOD1-mediated toxicity by modulating proteostasis.
Int'l Joint Research
(of which Int'l Joint Research: 4 results,
Peer Reviewed: 6 results,
Open Access: 3 results,
Acknowledgement Compliant: 2 results)
(of which Int'l Joint Research: 11 results,
Invited: 3 results)
Tokai J. Exp. Clin. Med.
Hum Mol Genet.
Front. Mol. Neurosci.
Amyotroph. Lateral Scler. Frontotempo. Degen.
Volume: in press
Attribution of KAKENHI