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Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms.
Neuron ( IF 16.2 ) Pub Date : 2020-03-12 , DOI: 10.1016/j.neuron.2020.02.021
Hyung-Lok Chung 1 , Michael F Wangler 2 , Paul C Marcogliese 3 , Juyeon Jo 4 , Thomas A Ravenscroft 3 , Zhongyuan Zuo 3 , Lita Duraine 5 , Sina Sadeghzadeh 6 , David Li-Kroeger 3 , Robert E Schmidt 7 , Alan Pestronk 7 , Jill A Rosenfeld 8 , Lindsay Burrage 8 , Mitchell J Herndon 7 , Shan Chen 8 , , Amelle Shillington 9 , Marissa Vawter-Lee 10 , Robert Hopkin 9 , Jackeline Rodriguez-Smith 11 , Michael Henrickson 11 , Brendan Lee 8 , Ann B Moser 12 , Richard O Jones 12 , Paul Watkins 12 , Taekyeong Yoo 13 , Soe Mar 14 , Murim Choi 15 , Robert C Bucelli 16 , Shinya Yamamoto 17 , Hyun Kyoung Lee 18 , Carlos E Prada 9 , Jong-Hee Chae 19 , Tiphanie P Vogel 20 , Hugo J Bellen 21
Affiliation  

ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme of the very-long-chain fatty acid (VLCFA) β-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.

中文翻译:

ACOX1中的功能丧失或获得功能突变会通过不同的机制导致轴突丧失。

ACOX1(酰基辅酶A氧化酶1)编码过氧化物酶体中超长链脂肪酸(VLCFA)β-氧化途径的第一个酶和限速酶,并导致产生H2O2。出乎意料的是,果蝇(d)ACOX1主要在胶质细胞中表达和需要,而ACOX1的丧失会导致发育延迟,p死亡,寿命缩短,突触传递受损以及神经胶质和轴突丧失。在ACOX1(p.N237S)中携带先前未确认的,从头开始的显性变异体的患者也表现出神经胶质丧失。但是,此突变导致ACOX1蛋白和功能水平升高,导致果蝇和鼠雪旺细胞中的胶质细胞中活性氧水平升高。ACOX1(p.N237S)患者表现出雪旺氏细胞和神经元严重丧失。然而,用抗氧化剂处理果蝇和雪旺氏原代细胞可抑制p。N237S诱导的神经变性。总之,ACOX1的丢失和获得都会导致神经胶质和神经元的丢失,但是不同的机制起作用,需要不同的治疗方法。
更新日期:2020-03-12
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