A burning question from the first international BPAN symposium: is restoration of autophagy a promising therapeutic strategy for BPAN?

Abstract

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disease associated with severe cognitive and motor deficits. BPAN pathophysiology and phenotypic spectrum are still emerging due to the fact that mutations in the WDR45 (WD repeat domain 45) gene, a regulator of macroautophagy/autophagy, were only identified a decade ago. In the first international symposium dedicated to BPAN, which was held in Lyon, France, a panel of international speakers, including several researchers from the autophagy community, presented their work on human patients, cellular and animal models, carrying WDR45 mutations and their homologs. Autophagy researchers found an opportunity to explore the defective function of autophagy mechanisms associated with WDR45 mutations, which underlie neuronal dysfunction and early death. Importantly, BPAN is one of the few human monogenic neurological diseases targeting a regulator of autophagy, which raises the possibility that it is a relevant model to directly assess the roles of autophagy in neurodegeneration and to develop autophagy restorative therapeutic strategies for more common disorders.Abbreviations: ATG: autophagy related; BPAN: beta-propeller protein-associated neurodegeneration; ER: endoplasmic reticulum; KO: knockout; NBIA: neurodegeneration with brain iron accumulation; PtdIns3P: phosphatidylinositol-3-phosphate; ULK1: unc-51 like autophagy activating kinase 1; WDR45: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting.

Keywords: Brain; ferritinophagy; iron; macroautophagy; neurological disease; therapy.

Figure 1.

The role of WDR45 in autophagy. (A) Schematic representation and 3D structure of WDR45. The 3D structure was generated by Alpha fold structure prediction. The 3D structure of WDR45 and WIPI1, WIPI2 and WDR45B/WIPI3 are similar in which the 7 WD repeats of WDR45 fold into a beta propeller [22]. WD1 to WD7 repeats are represented with the same color codes in the schematic and the 3D structure representation. Mutated residues localized in the PtdIns3P and ATG2 binding domains are shown with red and blue stars, respectively. The mapping of the reported WDR45 variants is not shown but those variants are distributed throughout the protein domains with no particular hotspots [33]. WDR45 variants all lead to BPAN, with a broad phenotypic spectrum and varied severity. (B) Schematic representation of the autophagy process and WDR45 interaction partners. Under fed conditions, WDR45 interacts with ATG2 in a complex with AMPK and ULK1. In this complex, ULK1 is inactive. Upon starvation and activation of AMPK by STK11/LKB1, the AMPK-ULK1-ATG2-WDR45 complex dissociates. On the one hand, AMPK activates the ULK1 complex by its phosphorylation and also inhibits MTOR. This results in the activation of the class III phosphatidylinositol 3-kinase complex and PtdIns3P production. On the other hand, the WDR45-ATG2 part of the complex is dissociated from the rest of the complex and localizes at the nascent autophagosome, where it presumably promotes maturation. In addition, WDR45 by interacting with EPG5 favors the fusion of autophagosomes with lysosomes.