Cell-autonomous and non-cell-autonomous mechanisms of neurodegeneration in ALS

2015 Fiscal Year Final Research Report

• Project/Area Number: 25293020
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Keio University
• Principal Investigator: Misawa Hidemi 慶應義塾大学, 薬学部, 教授 (80219617)
• Co-Investigator(Renkei-kenkyūsha): YAMANAKA Koji 名古屋大学, 環境医学研究所, 教授 (80446533)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 運動ニューロン / 筋萎縮性側索硬化症 / 神経変性疾患 / アストロサイト / ミクログリア / オステオポンチン / 細胞外マトリクス / 選択的脆弱性

Outline of Final Research Achievements

Selective vulnerability in motor neuron (MN) subtypes is a fundamental aspect of amyotrophic lateral sclerosis (ALS). MNs are subdivided into three motor units; fast-fatigable (FF), fast fatigue-resistant (FR) and slow (S). In ALS, FF MNs are more vulnerable than FR and S MNs. We found that the extracellular matrix (ECM) protein osteopontin (OPN) is selectively expressed by FR and S MNs, whereas matrix metalloproteinase-9 (MMP-9) is expressed by FF MNs. OPN is accumulated as extracellular granules in ECM in ALS mouse models and a familial ALS case. In SOD1G93A mice, OPN/MMP-9 double positivity marks remodeled FR and S MNs destined to compensate for lost FF MNs before ultimately dying. Genetic ablation of OPN in SOD1G93A mice shows dichotomic effects; disease onset is delayed but disease progression is accelerated. OPN induced MMP-9 up-regulation via αvβ3 integrin. Our results demonstrate that OPN is involved in the second-wave neurodegeneration by up-regulating MMP-9 in ALS.

Free Research Field

神経薬理学