The molecular pathophysiology of WIPI4 mutation in BPAN disease

Abstract

Autophagy is a highly conserved cell renewal process that consists on the formation of a double membraned autophagosome that grows and engulfs a portion of the cytosol for the degradation of its components to yield anabolic precursors. The WIPI proteins, WIPI1 to WIPI4 are key autophagy effectors with distinct functions supporting the cellular process at various levels. This study will focus on WIPI4 and its involvement in human disease. BPAN is a neurodegeneration with brain iron accumulation (NBIA) subtype characterized by the presence of iron deposits in the Substantia nigra and Globus pallidus of patients’ brains. The symptoms associated with the disease include early onset parkinsonism, dystonia, intellectual disability and seizures. The condition is caused by the de novo mutation of WDR45, the gene encoding human WIPI4. Although loss of WIPI4 function is known to be the underlying cause of BPAN pathophysiology, the specific cellular mechanisms disrupted by WIPI4 mutation remain largely unknown. Several studies propose that loss of WIPI4 results in autophagy and hence, ferritinophagy disruption. Nevertheless, none has described the specific role of WIPI4 in this process. The aim of this study was to unravel the involvement of WIPI4 in ferritinophagy and iron homeostasis in the context of BPAN disease.

Die Dissertation ist gesperrt bis zum 10. Juli 2027 !