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

Acknowledgements

We would like to thank the French family associations “Autour du BPAN” and “BPAN France” for their permanent support to BM, MC, SA and LW.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

BPAN research was supported by “Autour du BPAN”, “BPAN France” JORISS, Fondation Groupama grants to BM, MC, SA and LW. MM, AP, BM and LW were supported by a grant from the Million Dollar Bike Ride program (MDBR-21-123-BPAN and MDBR-23-015-NBIABPAN). RI and BM were supported by Marie Skłodowska-Curie Actions (NeuroDiDro - 101067877 - DLV-101067877). RE was supported by grant number PID2021-127355OB-I00 (MCIN/AEI/10.13039/501100011033/FEDER). SJH was supported by the NBIA Disorders Association, Hoffungsbaum e.V., AISNAF, and Isabel's Chance.