Physiological Significance of WDR45, A Responsible Gene for β-propeller Protein Associated Neurodegeneration (BPAN), in Brain Development

Abstract

WDR45 plays an essential role in the early stage of autophagy. De novo heterozygous mutations in WDR45 have been known to cause b-propeller protein-associated neurodegeneration (BPAN), a subtype of neurodegeneration with brain iron accumulation (NBIA). Although BPAN patients display global developmental delay including intellectual disability, neurodevelopmental pathophysiology of BPAN remains largely unknown. In the present study, we analyzed the physiological role of Wdr45 and pathophysiological significance of the gene abnormality during mouse brain development. Morphological and biochemical analyses revealed that Wdr45 is expressed in a developmental stage-dependent manner in mouse brain. Wdr45 was also found to be located in the excitatory synapses in biochemical fractionation. Since the WDR45 mutations are thought to cause protein degradation, we conducted acute knockdown experiments by an in utero electroporation method with mice to recapitulate the pathophysiological conditions of BPAN. Silencing of Wdr45 caused abnormal dendritic development and synaptogenesis during corticogenesis, both of which were significantly rescued by co-expression with RNAi-resistant version of Wdr45. In addition, terminal arbors of callosal axons were less developed in Wdr45-deficient cortical neurons of adult mouse when compared to the control cells. These results strongly suggest a pathophysiological significance of WDR45 gene abnormalities in neurodevelopmental aspects of BPAN.

Expression Analyses of Polo-Like Kinase 4, a Gene Product Responsible for Autosomal Recessive Microcephaly and Seckel Syndrome, during Mouse Brain Development

“…The staining patterns of Plk4 in the cerebral cortex and hippocampal CA1 (Fig. 2C, b, b’, c, and c’) resemble those of molecules distributed in neuropils, such as spinophilin [19], guanylate kinase-associated protein [20], p140Cap [21], and Wdr45 [22], suggesting the Plk4 localization at excitatory synapses. On the contrary, Plk4 was barely detected in axon bundles in the striatum (Fig.…”

Skewed X-chromosome Inactivation in Women with Idiopathic Intellectual Disability is Indicative of Pathogenic Variants

“…Therefore, the expression of P/LP variants may result in the accumulation of intracellular debris, affecting the functioning of the affected tissue. Such accumulations tend to primarily impair the central nervous system due to iron assembling in brain tissue and may impact global development, causing ID and cognitive degeneration [37,38]. Skewed X-chromosome inactivation in women carrying WDR45 variants have been previously reported, in which only the mutated alleles were detected [7,40,41].…”

Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis inDrosophilaand Vici Syndrome patients

“…Despite considerable clinical variability, these disorders are typically characterized by a neurodegenerative component of variable onset superimposed on an early-onset neurodevelopmental disorder. The natural history of neurological features in VS and related congenital disorders of autophagy such as beta-propeller protein-associated neurodegeneration (BPAN) [19][20][21][22] raises thus the question if the epilepsy commonly observed in these conditions is simply secondary to the principal neurodevelopmental defect and/or driven by the superimposed neurodegenerative component.…”