Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease

International Journal of Molecular Sciences

Linlin Ma¹  Des R. Richardson¹  Vladimir N. Uversky²  Matthew K. Boag³  Angus Roberts³  Dean L. Pountney³ 

[1] Griffith Institute of Drug Discovery, Griffith University, Nathan 4111, Australia;Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;School of Pharmacy and Medical Science, Griffith University, Gold Coast 4222, Australia;

关键词: α-synuclein;    ferritin;    iron;    autophagy;    ferritinophagy;    vesicular trafficking;   

DOI  :  10.3390/ijms23042378

来源: DOAJ

【 摘 要 】

A major hallmark of Parkinson’s disease (PD) is the fatal destruction of dopaminergic neurons within the substantia nigra pars compacta. This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution of α-synuclein aggregation, iron accumulation, and mitochondrial dysfunction plague nigral neurons, yet the events underlying iron accumulation are poorly understood. Elevated intracellular iron concentrations up-regulate ferritin expression, an iron storage protein that provides cytoprotection against redox stress. The lysosomal degradation pathway, autophagy, can release iron from ferritin stores to facilitate its trafficking in a process termed ferritinophagy. Aggregated α-synuclein inhibits SNARE protein complexes and destabilizes microtubules to halt vesicular trafficking systems, including that of autophagy effectively. The scope of this review is to describe the physiological and pathological relationship between iron regulation and α-synuclein, providing a detailed understanding of iron metabolism within nigral neurons. The underlying mechanisms of autophagy and ferritinophagy are explored in the context of PD, identifying potential therapeutic targets for future investigation.

【 授权许可】

Unknown