In 2006, GRN mutations were first linked to frontotemporal dementia (FTD), the leading cause of non-Alzheimer dementias. While much research has been dedicated to understanding the genetic causes of the disease, our understanding of the mechanistic impacts of GRN deficiency has only recently begun to take shape. With no known cure or treatment available for GRN-related FTD, there is a growing need to rapidly advance genetic and/or small-molecule therapeutics for this disease. This issue is complicated by the fact that, while lysosomal dysfunction seems to be a key driver of pathology, the mechanisms linking a loss of GRN to a pathogenic state remain unclear. In our attempt to address these key issues, we have turned to the nematode, Caenorhabditis elegans, to model, study, and find potential therapies for GRN-deficient FTD. First, we show that the loss of the nematode GRN ortholog, pgrn-1, results in several behavioral and molecular defects, including lysosomal dysfunction and defects in autophagic flux. Our investigations implicate the sphingolipid metabolic pathway in the regulation of many of the in vivo defects associated with pgrn-1 loss. Finally, we utilized these nematodes as an in vivo tool for high-throughput drug screening and identified two small molecules with potential therapeutic applications against GRN/pgrn-1 deficiency. These compounds reverse the biochemical, cellular, and functional phenotypes of GRN deficiency. Together, our results open avenues for mechanistic and therapeutic research into the outcomes of GRN-related neurodegeneration, both genetic and molecular.

2006 年，GRN突变首次与额颞叶痴呆 (FTD) 相关，后者是非阿尔茨海默病痴呆的主要原因。虽然许多研究致力于了解该疾病的遗传原因，但我们对GRN缺乏的机制影响的理解直到最近才开始形成。由于GRN相关的 FTD尚无已知的治愈或治疗方法，因此越来越需要快速推进该疾病的基因和/或小分子疗法。这个问题因为溶酶体功能障碍似乎是病理的关键驱动因素而变得复杂，但将GRN缺失与致病状态联系起来的机制仍不清楚。在我们试图解决这些关键问题的过程中，我们转向了线虫，Caenorhabditis elegans，用于建模、研究和寻找GRN缺陷型FTD 的潜在疗法。首先，我们表明线虫GRN直系同源物pgrn-1的缺失会导致一些行为和分子缺陷，包括溶酶体功能障碍和自噬通量缺陷。我们的研究表明鞘脂代谢途径在调节与pgrn-1丢失相关的许多体内缺陷中。最后，我们利用这些线虫作为高通量药物筛选的体内工具，并鉴定了两种具有潜在治疗应用的小分子GRN / pgrn-1不足。这些化合物可逆转GRN缺乏症的生化、细胞和功能表型。总之，我们的研究结果为GRN相关神经退行性变（遗传和分子）结果的机制和治疗研究开辟了道路。