Berggren Kiersten L, Lu Zhen, Fox Julia A, Dudenhoeffer Megan, Agrawal Sonal, Fox Jonathan H
Department of Veterinary Sciences, University of Wyoming, Laramie, WY, USA.
Neuroscience Graduate Program, University of Wyoming, Laramie, WY, USA.
J Huntingtons Dis. 2016;5(1):53-63. doi: 10.3233/JHD-150182.
Dysregulation of iron homeostasis is implicated in the pathogenesis of Huntington's disease. We have previously shown that increased iron intake in R6/2 HD neonatal mice, but not adult R6/2 HD mice potentiates disease outcomes at 12-weeks of age corresponding to advanced HD [Redox Biol. 2015;4 : 363-74]. However, whether these findings extend to other HD models is unknown. In particular, it is unclear if increased neonatal iron intake can promote neurodegeneration in mouse HD models where disease onset is delayed to mid-adult life.
To determine if increased dietary iron intake in neonatal and adult life-stages potentiates HD in the slowly progressive YAC128 HD mouse model.
Female neonatal mice were supplemented daily from days 10-17 with 120μg/g body weight of carbonyl iron. Adult mice were provided diets containing low (50 ppm), medium (150 ppm) and high (500 ppm) iron concentrations from 2-months of age. HD progression was determined using behavioral, brain morphometric and biochemical approaches.
Neonatal-iron supplemented YAC128 HD mice had significantly lower striatal volumes and striatal neuronal cell body volumes as compared to control HD mice at 1-year of age. Neonatal-iron supplementation of HD mice had no effect on rota-rod motor endurance and brain iron or glutathione status. Adult iron intake level had no effect on HD progression. YAC128 HD mice had altered peripheral responses to iron intake compared to iron-matched wild-type controls.
Female YAC128 HD mice supplemented with nutritionally-relevant levels of iron as neonates demonstrate increased striatal degeneration 1-year later.
铁稳态失调与亨廷顿舞蹈病的发病机制有关。我们之前已经表明，R6/2型亨廷顿舞蹈病新生小鼠铁摄入量增加会加重疾病结局，但成年R6/2型亨廷顿舞蹈病小鼠则不会，这与12周龄时晚期亨廷顿舞蹈病的情况相符[《氧化还原生物学》。2015年；4：363 - 74]。然而，这些发现是否适用于其他亨廷顿舞蹈病模型尚不清楚。特别是，目前尚不清楚在疾病发病延迟至成年中期的小鼠亨廷顿舞蹈病模型中，新生儿期铁摄入量增加是否会促进神经退行性变。
确定在缓慢进展的YAC128型亨廷顿舞蹈病小鼠模型中，新生儿期和成年期饮食中铁摄入量增加是否会加重亨廷顿舞蹈病。
雌性新生小鼠从出生后第10天至第17天每天补充120μg/g体重的羰基铁。成年小鼠从2月龄开始食用含铁浓度低（50ppm）、中（150ppm）和高（500ppm）的饲料。使用行为学、脑形态学和生物化学方法确定亨廷顿舞蹈病的进展情况。
与1岁时的对照亨廷顿舞蹈病小鼠相比，补充新生儿期铁的YAC128型亨廷顿舞蹈病小鼠的纹状体体积和纹状体神经元细胞体体积显著更小。对亨廷顿舞蹈病小鼠补充新生儿期铁对转棒运动耐力以及脑铁或谷胱甘肽状态没有影响。成年期铁摄入量对亨廷顿舞蹈病进展没有影响。与铁含量匹配的野生型对照相比，YAC128型亨廷顿舞蹈病小鼠对外周铁摄入的反应有所改变。
新生期补充营养相关水平铁的雌性YAC128型亨廷顿舞蹈病小鼠在1年后纹状体变性增加。
