WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death

Abstract

Mutations in the autophagy gene WDR45 cause -propeller protein-associated neurodegeneration (BPAN); however the molecular and cellular mechanism of the disease process is largely unknown. Here we generated constitutive Wdr45 knockout (KO) mice that displayed cognitive impairments, abnormal synaptic transmission and lesions in hippocampus and basal ganglia. Immunohistochemistry analysis shows loss of neurons in prefrontal cortex and basal ganglion in aged mice, and increased apoptosis in these regions, recapitulating a hallmark of neurodegeneration. Quantitative proteomic analysis shows accumulation of endoplasmic reticulum (ER) proteins in KO mouse. Furthermore, we show that a defect in autophagy results in impaired ER turnover and ER stress. The unfolded protein response (UPR) is elevated through IRE1 and possibly other kinase signaling pathways, and eventually leads to neuronal apoptosis. Suppression of ER stress, or activation of autophagy through inhibition of mTOR pathway rescues neuronal death. Thus, our study not only provides mechanistic insights for BPAN, but also suggests that a defect in macroautophagy machinery leads to impairment in selective organelle autophagy.

Neuronal autophagy regulates presynaptic neurotransmission by controlling the axonal endoplasmic reticulum

“…Accumulation of the ER with associated neurodegeneration has been observed in CRISPR KO mice constitutively lacking the autophagy regulatory factor WDR45 (Wan et al, 2020). Our findings are consistent with this and further suggest that ER-phagy is a major autophagic process in neurons in the absence of proteotoxic challenges at steady-state.…”

Elevating sestrin2 attenuates endoplasmic reticulum stress and improves functional recovery through autophagy activation after spinal cord injury

“…Previous studies demonstrated that restoring ER function is one of the available strategies for acute CNS injury, as it helps neuron against ER stress induced apoptosis [24,25]. In the present study, we also identified that upregulation of sestrin2 by AAV provides beneficial effects on reducing ER stress and apoptosis.…”

“…Though unfolded protein response (UPR) provides effect on attenuating misfolded proteins, durative ER stress without treatment ultimately exceeds the compensation and turns UPR into pro-death [22,23]. Accordingly, maintaining ER homeostasis is available for neuron regeneration and function [24,25]. In particular, a study reported by park et al [26] showed that ER stress suppressed by sestrin2 is important for hepatic rehabilitation.…”

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

“…In particular, the WDR45 protein, by binding to phosphatidylinositol-3-phosphate (PtdIns3P), regulates autophagosome formation [ 149 , 150 , 151 ]. In this way, defective autophagic flux associated with WDR45 mutations have been described in different cellular and animal studies [ 147 , 152 , 153 , 154 , 155 ]. KO mice for Wdr45 show an impaired autophagic flux with accumulation of SQSTM1- and ubiquitin-positive aggregates in neurons and swollen axons.…”

“…In BPAN patients’ fibroblasts, a positive regulation of the iron transporter IRE/DMT1 (iron responsive element–divalent metal transporter 1) and a negative regulation of the transferrin receptor have been found, like in other NBIA disorders [ 153 ]. In addition, an increase in intracellular Fe 2+ after starvation have been observed, which may explain the accumulation of iron in the basal ganglia due to defects in autophagy and recycling, and alterations in lysosomal degradation [ 153 ]. IPSC-derived midbrain neurons together with fibroblasts from a BPAN woman showed augmented levels of intracellular iron and reduced levels of L-ferritin, H-ferritin and mitochondrial ferritin.…”