Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms

被引：91

作者：

Chung, Hyung-lok ^{[1
,2
,3
]}

Wangler, Michael F. ^{[1
,2
,4
]}

Marcogliese, Paul C. ^{[1
,2
]}

Jo, Juyeon ^{[2
,5
]}

Ravenscroft, Thomas A. ^{[1
,2
]}

Zuo, Zhongyuan ^{[1
,2
]}

Duraine, Lita ^{[3
]}

Sadeghzadeh, Sina ^{[6
]}

Li-Kroeger, David ^{[1
,2
]}

Schmidt, Robert E. ^{[7
]}

Pestronk, Alan ^{[7
]}

Rosenfeld, Jill A. ^{[1
]}

Burrage, Lindsay ^{[1
]}

Herndon, Mitchell J. ^{[7
]}

Chen, Shan ^{[1
]}

Shillington, Amelle ^{[8
,9
]}

Vawter-Lee, Marissa ^{[9
,10
]}

Hopkin, Robert ^{[8
,9
]}

Rodriguez-Smith, Jackeline ^{[9
,11
]}

Henrickson, Michael ^{[9
,11
]}

Lee, Brendan ^{[1
]}

Moser, Ann B. ^{[12
]}

Jones, Richard O. ^{[12
]}

Watkins, Paul ^{[12
]}

Yoo, Taekyeong ^{[13
]}

Mar, Soe ^{[14
]}

Choi, Murim ^{[13
,15
]}

Bucelli, Robert C. ^{[16
]}

Yamamoto, Shinya ^{[1
,2
,4
,17
]}

Lee, Hyun Kyoung ^{[2
,4
,5
,17
]}

Prada, Carlos E. ^{[8
,9
]}

Chae, Jong-Hee ^{[15
]}

Vogel, Tiphanie P. ^{[18
]}

Bellen, Hugo J. ^{[1
,2
,3
,4
,17
]}

机构：

[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[2] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA

[3] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA

[4] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Pediat, Sect Neurol, Houston, TX 77030 USA

[6] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA

[7] Washington Univ, Dept Pathol & Immunol, Div Neuropathol, Sch Med, St Louis, MO 63110 USA

[8] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA

[9] Univ Cincinnati, Dept Pediat, Coll Med, Cincinnati, OH 45229 USA

[10] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH 45229 USA

[11] Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH 45229 USA

[12] Johns Hopkins Sch Med, Kennedy Krieger Inst, Div Neurogenet, Baltimore, MD 21205 USA

[13] Seoul Natl Univ, Dept Biomed Sci, Coll Med, Seoul, South Korea

[14] Washington Univ, St Louis Childrens Hosp, Dept Neurol, Sch Med, St Louis, MO 63110 USA

[15] Seoul Natl Univ, Dept Pediat, Coll Med, Seoul, South Korea

[16] Washington Univ, Dept Neurol, Sch Med, St Louis, MO 63110 USA

[17] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA

[18] Texas Childrens Hosp, Baylor Coll Med, Ctr Human Immunobiol, Dept Pediat,Sect Rheumatol, Houston, TX 77030 USA

来源：

NEURON | 2020年 / 106卷 / 04期

关键词：

CHAIN FATTY-ACIDS; PEROXISOMAL BETA-OXIDATION; N-ACETYLCYSTEINE AMIDE; MOUSE MODEL; LIPID-PEROXIDATION; ACYL-COENZYME; SCHWANN-CELLS; DROSOPHILA; BIOGENESIS; PROTEIN;

D O I：

10.1016/j.neuron.2020.02.021

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme of the very-long-chain fatty acid (VLCFA) beta-oxidation pathway in peroxisomes and leads to H2O2 production. Unexpectedly, Drosophila (d) ACOX1 is mostly expressed and required in glia, and loss of ACOX1 leads to developmental delay, pupal death, reduced lifespan, impaired synaptic transmission, and glial and axonal loss. Patients who carry a previously unidentified, de novo, dominant variant in ACOX1(p.N237S) also exhibit glial loss. However, this mutation causes increased levels of ACOX1 protein and function resulting in elevated levels of reactive oxygen species in glia in flies and murine Schwann cells. ACOX1 (p.N237S) patients exhibit a severe loss of Schwann cells and neurons. However, treatment of flies and primary Schwann cells with an antioxidant suppressed the p.N237S-induced neurodegeneration. In summary, both loss and gain of ACOX1 lead to glial and neuronal loss, but different mechanisms are at play and require different treatments.

引用

页码：589 / +

页数：24

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