Bouillet Philippe, Robati Mikara, Adams Jerry M, Strasser Andreas
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
J Neurosci Res. 2003 Dec 1;74(5):777-81. doi: 10.1002/jnr.10805.
Lurcher (lc) mice have a semi-dominant mutation in the gene encoding the delta2 glutamate receptor (GRID2). The resulting constitutive activity of this receptor in heterozygous +/lc (grid(+/lc)) and homozygous (grid(lc/lc)) mice leads to the death of all cerebellar Purkinje cells and most afferent granule neurons. Some studies have indicated that the death of Purkinje cells occurs by apoptosis, and the secondary loss of granule neurons has been shown to require the pro-apoptotic Bcl-2 family member Bax. The BH3-only protein Bim has been shown to contribute to cytokine withdrawal-induced apoptosis of sympathetic neurons and to be responsible for the kidney degeneration in mice lacking the pro-survival protein Bcl-2. Because Bim is expressed strongly in cerebellar Purkinje cells, we have examined whether it has a role in their death in mutant Lurcher mice. Our studies show that Bim deficiency does not modify the Lurcher phenotype, ruling out an indispensable role for Bim in this neurodegenerative disease.
Lurcher（lc）小鼠在编码δ2谷氨酸受体（GRID2）的基因中存在半显性突变。这种受体在杂合子+/lc（grid(+/lc)）和纯合子（grid(lc/lc)）小鼠中产生的组成性活性导致所有小脑浦肯野细胞和大多数传入颗粒神经元死亡。一些研究表明，浦肯野细胞的死亡是通过凋亡发生的，并且颗粒神经元的继发性丧失已被证明需要促凋亡的Bcl-2家族成员Bax。仅含BH3结构域的蛋白Bim已被证明有助于细胞因子撤除诱导的交感神经元凋亡，并导致缺乏促生存蛋白Bcl-2的小鼠出现肾脏退化。由于Bim在小脑浦肯野细胞中强烈表达，我们研究了它在突变的Lurcher小鼠浦肯野细胞死亡中是否起作用。我们的研究表明，Bim缺陷不会改变Lurcher表型，排除了Bim在这种神经退行性疾病中的不可或缺的作用。
