Elucidating cellular mechanisms underlying neurodegeneration

巨轴突神经病（GAN）是一种早发性常染色体隐性遗传神经退行性疾病， 影响中枢和外周神经系统在病理学上，GAN的特征是 中间纤维的解体和聚集（IF）。IF由自组装亚基形成 网络从细胞核到细胞外围。在GAN中，许多细胞类型显示出异常， IF的组织，但神经元显然首当其冲的病理。轴突随着 神经元IF，并退化导致GAN的神经症状。GAN中突变的基因编码 gigaxonin，一种属于E3连接酶样衔接蛋白的BTB/Kelch家族的蛋白。这些蛋白质 通常在泛素-蛋白酶体介导的蛋白质降解中起作用。根据我们自己的数据， 我们假设神经丝的聚集在神经突起中产生了空间障碍， 干扰细胞器如线粒体和溶酶体的细胞内转运，导致 下游病理学此外，我们的初步数据表明，gigaxonin在自噬中起直接作用 通过降解其他基质。我们假设，这一关键过程的中断加剧了 通过蛋白质失调和细胞器质量控制的GAN神经病理学。该提案全面 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 以期激发新的治疗策略。

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.