Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer.
Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer.
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DOI：
10.1038/s41467-018-05972-1
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发表时间：
2018-08-29
影响因子：
16.6
通讯作者：
Waddington SN
中科院分区：
文献类型：
--
作者：
Baruteau J;Perocheau DP;Hanley J;Lorvellec M;Rocha-Ferreira E;Karda R;Ng J;Suff N;Diaz JA;Rahim AA;Hughes MP;Banushi B;Prunty H;Hristova M;Ridout DA;Virasami A;Heales S;Howe SJ;Buckley SMK;Mills PB;Gissen P;Waddington SN
精氨基琥珀酸裂解酶（ASL）属于肝脏尿素循环解毒氨，瓜氨酸-一氧化氮（NO）循环产生NO。ASL缺乏患者出现精氨基琥珀酸尿症，其特征为高氨血症、多器官疾病和神经认知障碍，尽管治疗旨在使氨血症正常化，但未考虑NO失衡。在这里，我们表明，大脑疾病的氨基琥珀酸尿症涉及神经元氧化/亚硝化应激独立的高氨血症。将AAV 8载体静脉注射到成年或新生ASL缺陷小鼠中分别证明了肝脏尿素循环和大脑瓜氨酸-NO循环的长期校正。如果氨血症仅正常化，脑疾病持续存在，但在纠正氨血症和神经元ASL活性后，脑疾病显著减少。这与行为改善和减少皮质细胞死亡相关。因此，神经元氧化/亚硝化应激是与高氨血症不同的病理生理机制。利用一种载体同时进行脑和肝基因转移，治疗两种代谢途径，从而改善疾病，为肝脑代谢疾病提供了新的希望。ASL基因突变的患者表现为以高氨血症和认知障碍为特征的氨基琥珀酸尿症。在这里，作者表明，脑疾病涉及神经元亚硝化/氧化应激，这不是由高氨血症引起的，并且可以使用针对小鼠肝脏和大脑的AAV-ASL逆转。
Argininosuccinate lyase (ASL) belongs to the hepatic urea cycle detoxifying ammonia, and the citrulline-nitric oxide (NO) cycle producing NO. ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia, multiorgan disease and neurocognitive impairment despite treatment aiming to normalise ammonaemia without considering NO imbalance. Here we show that cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress independent of hyperammonaemia. Intravenous injection of AAV8 vector into adult or neonatal ASL-deficient mice demonstrates long-term correction of the hepatic urea cycle and the cerebral citrulline-NO cycle, respectively. Cerebral disease persists if ammonaemia only is normalised but is dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This correlates with behavioural improvement and reduced cortical cell death. Thus, neuronal oxidative/nitrosative stress is a distinct pathophysiological mechanism from hyperammonaemia. Disease amelioration by simultaneous brain and liver gene transfer with one vector, to treat both metabolic pathways, provides new hope for hepatocerebral metabolic diseases. Patients with mutations in the ASL gene present with argininosuccinic aciduria characterised by hyperammonaemia and cognitive impairment. Here, the authors show that cerebral disease involves neuronal nitrosative/oxidative stress that is not induced by hyperammonaemia, and that it can be reversed using AAV-ASL directed to liver and brain in mice.
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影响因子：
12.4
作者：
Cunningham, Sharon C.;Kok, Cindy Y.;Alexander, Ian E.
通讯作者：
Alexander, Ian E.
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
5.1
作者：
Chandler, R. J.;Tarasenko, T. N.;McGuire, P. J.
通讯作者：
McGuire, P. J.
影响因子：
25.7
作者：
Hanley J;Dhar DK;Mazzacuva F;Fiadeiro R;Burden JJ;Lyne AM;Smith H;Straatman-Iwanowska A;Banushi B;Virasami A;Mills K;Lemaigre FP;Knisely AS;Howe S;Sebire N;Waddington SN;Paulusma CC;Clayton P;Gissen P
通讯作者：
Gissen P
影响因子：
3.4
作者：
Costes, SV;Daelemans, D;Lockett, S
通讯作者：
Lockett, S