Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, USA.
Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, USA; Touro University California, Vallejo, USA.
Neurobiol Dis. 2020 Jun;139:104786. doi: 10.1016/j.nbd.2020.104786. Epub 2020 Feb 5.
Mutations in the human ATP13A2 gene are associated with an early-onset form of Parkinson's disease (PD) known as Kufor Rakeb Syndrome (KRS). Patients with KRS show increased iron deposition in the basal ganglia, suggesting iron toxicity-induced neurodegeneration as a potential pathogenesis associated with the ATP13A2 mutation. Previously we demonstrated that functional losses of ATP13A2 disrupt the lysosomes ability to store excess iron, leading to reduce survival of dopaminergic neuronal cells. To understand the possible mechanisms involved, we studied a Caenorhabditis elegans mutant defective in catp-6 function, an ortholog of human ATP13A2 gene. Here we show that catp-6 mutant worms have defective autophagy and lysosomal function, demonstrate characteristic PD phenotypes including reduced motor function and dysregulated iron metabolism. Additionally, these mutants have defective mitochondrial health, which is rescuable via iron chelation or mitophagy induction.
人类 ATP13A2 基因突变与一种称为 Kufor Rakeb 综合征 (KRS) 的早发性帕金森病 (PD) 有关。KRS 患者的基底神经节铁沉积增加，表明铁毒性诱导的神经退行性变可能是与 ATP13A2 突变相关的潜在发病机制。我们之前的研究表明，ATP13A2 的功能丧失会破坏溶酶体储存多余铁的能力，导致多巴胺能神经元细胞存活率降低。为了了解可能涉及的机制，我们研究了一种在 catp-6 功能上有缺陷的秀丽隐杆线虫突变体，该基因是人类 ATP13A2 基因的同源物。在这里，我们展示了 catp-6 突变体线虫存在自噬和溶酶体功能缺陷，并表现出包括运动功能降低和铁代谢失调在内的典型 PD 表型。此外，这些突变体还存在线粒体健康缺陷，可通过铁螯合或线粒体自噬诱导来挽救。
