In this recent study, scientists from the Helmholtz Center Munich generated and extensively characterized a new mouse model for the rare neurological disorder Beta-Propeller Protein Associated Neurodegeneration (BPAN).
The WDR45 (WD Repeat Domain 45) gene encodes a beta-propeller scaffold protein with a putative role in autophagy, and several pathogenic variants are the genetic cause of this neurological disorder characterized by increased iron deposition in the basal ganglia in humans.
First, the researchers developed a model in which Wdr45 has been systemically knocked out using transcription activator-like effector nucleases (TALENs). Homozygous females and hemizygous males are viable, proving that systemic depletion of Wdr45 does not impair viability and male fertility in mice. The in-depth phenotypic characterization of the mouse model revealed neuropathology signs at four months of age, neurodegeneration progressing with ageing, hearing and visual impairment, hematological alterations, but no brain iron accumulation. Biochemically, Wdr45 KO mice presented with decreased complex I (CI) activity in the brain, suggesting that mitochondrial dysfunction accompanies Wdr45 deficiency.
The strength of this study is the systematical investigation of all clinical relevant organs. The analysis pointed out clinical chemical parameters (glucose, ASAT, LDH, ALP) and hematology values (RDW) that could potentially be used as biomarkers of BPAN in the perspective of using the BPAN model for treatment approaches, as they are easy to access in living animals. Increased levels of ASAT and LDH have been recently reported in a group of BPAN patients and were suggested as possible biomarkers of the disease (Belohlavkova et al. 2020).
The systemic Wdr45 KO mutants described represents a robust model to investigate pleiotropic features and the pathophysiology of the human variants, and further open up possibilities to test therapeutic approaches.
Biagosch CA, Vidali S, Faerberboeck M, Hensler SV, Becker L, Amarie OV, Aguilar-Pimentel A, Garrett L, Klein-Rodewald T, Rathkolb B, Zanuttigh E, Calzada-Wack J, da Silva-Buttkus P, Rozman J, Treise I, Fuchs H, Gailus-Durner V, de Angelis MH, Janik D, Wurst W, Mayr JA, Klopstock T, Meitinger T, Prokisch H, Iuso A. A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse. Mamm Genome. 2021 May 27. doi: 10.1007/s00335-021-09875-3. Epub ahead of print. PMID: 34043061.