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.

中文翻译：

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线虫 catp-6/ATP13A2 突变体中铁代谢失调会损害线粒体功能。


人类 ATP13A2 基因突变与早发型帕金森病 (PD)（称为库福拉克综合征 (KRS)）相关。 KRS 患者基底神经节铁沉积增加，表明铁毒性诱导的神经变性是与 ATP13A2 突变相关的潜在发病机制。此前我们证明，ATP13A2 的功能丧失会破坏溶酶体储存过量铁的能力，导致多巴胺能神经元细胞的存活率降低。为了了解所涉及的可能机制，我们研究了一种具有 catp-6 功能缺陷的秀丽隐杆线虫突变体，catp-6 是人类 ATP13A2 基因的直系同源物。在这里，我们发现catp-6突变线虫具有缺陷的自噬和溶酶体功能，表现出特征性的PD表型，包括运动功能降低和铁代谢失调。此外，这些突变体的线粒体健康有缺陷，可以通过铁螯合或线粒体自噬诱导来挽救。