Abstract：
Spinocerebellar ataxia 34 (SCA34) is an autosomal dominant disease that arises from point mutations in the fatty acid elongase, Elongation of Very Long Chain Fatty Acids 4 (ELOVL4), which is essential for the synthesis of Very Long Chain-Saturated Fatty Acids (VLC-SFA) and Very Long Chain-Polyunsaturated Fatty Acids (VLC-PUFA) (28-34 carbons long). SCA34 is considered a neurodegenerative disease. However, a novel rat model of SCA34 (SCA34-KI rat) with knock-in of the W246G ELOVL4 mutation that causes human SCA34 shows early motor impairment and aberrant synaptic transmission and plasticity without overt neurodegeneration. ELOVL4 is expressed in neurogenic regions of the developing brain, is implicated in cell cycle regulation, and ELOVL4 mutations that cause neuroichthyosis lead to developmental brain malformation, suggesting that aberrant neuron generation due to ELOVL4 mutations might contribute to SCA34. To test whether W246G ELOVL4 altered neuronal generation or survival in the cerebellum, we compared the numbers of Purkinje cells, unipolar brush cells, molecular layer interneurons, granule and displaced granule cells in the cerebellum of wildtype, heterozygous, and homozygous SCA34-KI rats at four months of age, when motor impairment is already present. An unbiased, semi-automated method based on Cellpose 2.0 and ImageJ was used to quantify neuronal populations in cerebellar sections immunolabeled for known neuron-specific markers. Neuronal populations and cortical structure were unaffected by the W246G ELOVL4 mutation by four months of age, a time when synaptic and motor dysfunction are already present, suggesting that SCA34 pathology originates from synaptic dysfunction due to VLC-SFA deficiency, rather than aberrant neuronal production or neurodegeneration.
摘要：
脊髓小脑共济失调34（SCA34）是一种常染色体显性疾病，由脂肪酸延伸酶的点突变引起，超长链脂肪酸4（ELOVL4）的延伸，这对于合成超长链饱和脂肪酸(VLC-SFA)和超长链多不饱和脂肪酸(VLC-PUFA)(28-34碳长)是必需的。SCA34被认为是一种神经退行性疾病。然而,导致人类SCA34的W246GELOVL4突变敲入的新型SCA34大鼠模型(SCA34-KI大鼠)显示早期运动损伤和异常突触传递和可塑性,而没有明显的神经变性.ELOVL4在发育中的大脑的神经区域表达，与细胞周期调节有关，和ELOVL4突变导致神经囊虫病导致发育性大脑畸形，提示由于ELOVL4突变导致的异常神经元生成可能有助于SCA34。为了测试W246GELOVL4是否改变了小脑中的神经元生成或存活，我们比较了浦肯野细胞的数量,单极刷细胞，分子层中间神经元，野生型小脑中的颗粒和置换的颗粒细胞，杂合子，和四个月龄的纯合SCA34-KI大鼠，当运动障碍已经存在时。一个不偏不倚的人，基于Cellpose2.0和ImageJ的半自动方法用于定量小脑切片中已知神经元特异性标记的神经元群体。到四个月龄时，神经元种群和皮质结构不受W246GELOVL4突变的影响，突触和运动障碍已经存在的时候，提示SCA34病理起源于VLC-SFA缺乏导致的突触功能障碍，而不是异常的神经元产生或神经变性。
