Molecular mechanism for the maintenance of proteostasis in motor neurons

2016 Fiscal Year Final Research Report

• Project/Area Number: 26290018
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Tokai University
• Principal Investigator: HADANO SHINJI 東海大学, 医学部, 教授 (60281375)
• Co-Investigator(Kenkyū-buntansha): 大友 麻子 東海大学, 医学部, 助教 (50535226)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 脳神経疾患 / 脳・神経 / 神経科学 / 遺伝子発現 / 蛋白質分解 / 酸化ストレス / 運動ニューロン / ALS

Outline of Final Research Achievements

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.

Free Research Field

総合領域・脳神経科学