Selective Expression of Osteopontin in ALS-resistant Motor Neurons is a Critical Determinant of Late Phase Neurodegeneration Mediated by Matrix Metalloproteinase-9

被引：58

作者：

Morisaki, Yuta ^{[1
]}

Niikura, Mamiko ^{[1
]}

Watanabe, Mizuho ^{[1
]}

Onishi, Kosuke ^{[1
]}

Tanabe, Shogo ^{[1
]}

Moriwaki, Yasuhiro ^{[1
]}

Okuda, Takashi ^{[1
]}

Ohara, Shinji ^{[2
]}

Murayama, Shigeo ^{[3
]}

Takao, Masaki ^{[3
]}

Uchida, Sae ^{[4
]}

Yamanaka, Koji ^{[5
]}

Misawa, Hidemi ^{[1
]}

机构：

[1] Keio Univ, Div Pharmacol, Fac Pharm, Tokyo 1058512, Japan

[2] Chushin Matsumoto Hosp, Dept Neurol, Matsumoto Med Ctr, Matsumoto, Nagano 3990021, Japan

[3] Tokyo Metropolitan Inst Gerontol, Dept Neuropathol, Tokyo 1730015, Japan

[4] Tokyo Metropolitan Inst Gerontol, Dept Auton Neurosci, Tokyo 1730015, Japan

[5] Nagoya Univ, Environm Med Res Inst, Dept Neurosci & Pathobiol, Nagoya, Aichi 4648601, Japan

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

关键词：

MOUSE MODEL; WILD-TYPE; CHOLINE-ACETYLTRANSFERASE; UNIT LOSS; DISEASE; ACETYLCHOLINE; INFLAMMATION; RECEPTOR; VULNERABILITY; PHAGOCYTOSIS;

D O I：

10.1038/srep27354

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Differential vulnerability among motor neuron (MN) subtypes is a fundamental feature of amyotrophic lateral sclerosis (ALS): fast-fatigable (FF) MNs are more vulnerable than fast fatigue-resistant (FR) or slow (S) MNs. The reason for this selective vulnerability remains enigmatic. We report here that the extracellular matrix (ECM) protein osteopontin (OPN) is selectively expressed by FR and S MNs and ALS-resistant motor pools, whereas matrix metalloproteinase-9 (MMP-9) is selectively expressed by FF MNs. OPN is secreted and accumulated as extracellular granules in ECM in three ALS mouse models and a human ALS patient. In SOD1(G93A) 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 delayed disease onset but then accelerated disease progression. OPN induced MMP-9 up-regulation via alpha v beta 3 integrin in ChAT-expressing Neuro2a cells, and also induced CD44-mediated astrocyte migration and microglial phagocytosis in a non-cell-autonomous manner. Our results demonstrate that OPN expressed by FR/S MNs is involved in the second-wave neurodegeneration by up-regulating MMP-9 through alpha v beta 3 integrin in the mouse model of ALS. The differences in OPN/MMP-9 expression profiles in MN subsets partially explain the selective MN vulnerability in ALS.

引用

页数：19

共 65 条

[1] Acetylcholine induces neurite outgrowth and modulates matrix metalloproteinase 2 and 9 [J].