Elucidating cellular mechanisms underlying neurodegeneration

巨大轴索神经病(GAN)是一种起病早、常染色体隐性遗传的神经退行性疾病。 影响中枢和外周神经系统。从病理上讲，GaN的特征是 中间细丝的解体和聚集(IF)。由自组装亚单位组成的IF 网络横跨细胞，从细胞核到外围。在GaN中，许多细胞类型显示出异常的 IF的组织，但神经元显然首当其冲的病理。轴突随着神经元的堆积而肿胀 神经元IF和退行性变引起GAN的神经症状。在GaN中突变的基因编码 一种属于BTB/Kelch家族的E3连接酶样适配子蛋白。这些蛋白质 通常在泛素-蛋白酶体介导的蛋白质降解中发挥作用。根据我们自己的数据，Gan 降解神经元IF，我们假设神经丝聚集在神经突起中造成空间障碍 干扰线粒体和溶酶体等细胞器的细胞内运输，导致 下游病理学。此外，我们的初步数据表明，神经生长素在自噬中起着直接作用。 通过降解其他底物。我们假设，这一关键进程的中断加剧了 蛋白质调节失调和细胞器质量控制引起的神经病理改变。这项建议全面 测试这些模型；因此，我们研究的总体目标是了解GaN的细胞发病机制 以期启发新的治疗策略。

Giant axonal neuropathy (GAN) is an early-onset, autosomal recessive neurodegenerative disease that impacts the central and peripheral nervous systems. Pathologically, GAN is characterized by the disorganization and aggregation of intermediate filaments (IF). Formed from self-assembling subunits, the IF network spans the cell from the nucleus to the periphery. In GAN, many cell types show abnormalities in the organization of IF, but neurons clearly bear the brunt of the pathology. Axons swell with the accumulation of neuronal IF, and degenerate to cause the neurological symptoms of GAN. The gene mutated in GAN encodes gigaxonin, a protein that belongs to the BTB/Kelch family of E3 ligase-like adaptor proteins. These proteins typically play a role in ubiquitin-proteasome mediated protein degradation. Based on our own data that GAN degrades neuronal IFs, we hypothesize that neurofilament aggregation creates steric roadblocks in neurites that interfere with intracellular transport of organelles such as mitochondria and lysosomes, resulting in downstream pathology. Furthermore, our preliminary data suggest gigaxonin plays a direct role in autophagy via degradation of other substrates. We hypothesize that the disruption of this critical process exacerbates GAN neuropathology by dysregulation of protein and organellar quality control. This proposal comprehensively tests these models; thus the overall goal of our research is to understand the cellular pathogenesis of GAN with a view to inspiring novel treatment strategies.