据3月13日的《科学》杂志报道说,根据一项新的研究披露,对一种造成阿尔茨海默病的基因的变异来说,如果某人从其双亲那里遗传了该种变异的基因的话,其罹患阿尔茨海默病的机会比仅从父母中一个人那里遗传该变异基因的机会要小。
研究发现,这种由单个基因变异而产生的保护性作用可能为治疗阿尔茨海默病提供新的途径。 这些发现还表明有这样的可能,即其它的被认为无害的基因变异如果被遗传了双份的话就可能会引起疾病。这进而表明,在一个具有该种疾病历史的家族中有必要进行遗传学的筛检。 在所有的阿尔茨海默症病例中,只有非常小的比例是因为遗传造成的,但这些病例常常会在生命的相对较早的时期出现并比该病的其它形式会更快地进展。 现在发现的是遗传性阿尔茨海默病的第一个已知的隐性基因变异;其它类型的已知基因变异都是显性的,即只要遗传有一份这样基因就足以引起该种疾病。 所有这些变异都发生在淀粉样蛋白前体(或称APP)之中,该蛋白前体会被多种酶切割成“β-淀粉样蛋白”片断,该蛋白片断会在阿尔茨海默病患者的脑中积聚。
Giuseppe Di Fede及其在意大利的同僚现在描述了一种叫做A673V的APP变异,它会导致β-淀粉样蛋白产生的增加并增加了β-淀粉样蛋白积聚的可能性,从而形成淀粉样的纤维。 但是,在杂合子患者中,正常蛋白与变异蛋白之间的相互作用有时会阻断这一变化,从而在实际上阻止了β-淀粉样蛋白的产生。 这一发现可能可以解释为什么杂合子基因携带者即使在非常老的年龄也不会得该种疾病。(生物谷Bioon.com)
生物谷推荐原始出处:
Science 13 March 2009:DOI: 10.1126/science.1168979
A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis
Giuseppe Di Fede,1 Marcella Catania,1 Michela Morbin,1 Giacomina Rossi,1 Silvia Suardi,1 Giulia Mazzoleni,1 Marco Merlin,1 Anna Rita Giovagnoli,1 Sara Prioni,1 Alessandra Erbetta,2 Chiara Falcone,3 Marco Gobbi,4 Laura Colombo,4 Antonio Bastone,4 Marten Beeg,4 Claudia Manzoni,4 Bruna Francescucci,5 Alberto Spagnoli,5 Laura Cantù,6 Elena Del Favero,6 Efrat Levy,7 Mario Salmona,4 Fabrizio Tagliavini1*
β-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced β-amyloid (Aβ) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Aβ aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.
1 Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
2 Division of Neuroradiology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
3 Division of Neuroepidemiology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
4 Department of Molecular Biochemistry and Pharmachology, Istituto di Ricerche Farmacologiche "Mario Negri," 20156 Milan, Italy.
5 Division of Cognitive Disorders, Centro Sant'Ambrogio Fatebenefratelli, Cernusco sul Naviglio, 20063 Milan, Italy.
6 Department of Medical Chemistry, Biochemistry, and Biotechnology, University of Milan, Segrate, 20090 Milan, Italy.
7 Departments of Pharmacology and Psychiatry, New York University School of Medicine, and Nathan S. Kline Institute, Orangeburg, NY 10962, USA.