WDR45 | BPAN ROS/LIPID PEROXIDATION
SOURCE: Glutamatergic Neuron-Liperfluo-CRISPRi CRISPRi FACS screen for oxidized lipids in human iPSC-derived glutamatergic neurons.
http://crisprbrain.org/simple-screen/?screen=HSPC-CD34-CRISPRn
(PREPRINT: This article is a preprint and has not been certified by peer review)
View ORCID Profile Ruilin Tian, Anthony Abarientos, Jason Hong, Sayed Hadi Hashemi, Rui Yan, Mike A. Nalls, Andrew B. Singleton, View ORCID Profile Ke Xu, Faraz Faghri, View ORCID Profile Martin Kampmann
Evolving BPAN/WDR45 related research centered on the role of ROS/lipid peroxidation as it pertains to affected iron and lysosome status has been recently reported in research publications.
Direct assays, screening and studies that are BPAN/WDR45 specific are limited, however a recent preprint of a study , "Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis", provides ongoing support of ROS/lipid peroxidation in BPAN/WDR45.
KEY FINDINGS OF STUDY:
Evidence of ROS/lipid peroxidation in WDR45 glutamatergic neurons which strongly affected iron and/or lysosome status lipid peroxidation levels in neurons and causes neuronal ferroptosis under oxidative stress
Knockdown of WDR45 gene affected both lysosomal status and iron levels, reflecting the key role of lysosomes in iron homeostasis
The research study screens and results are available through a publicly accessible database, http://crisprbrain.org/ which includes screens for Reactive Oxygen Species (CellRox Intensity) and Peroxidized Lipids (Liperfluo Intensity) through the Kampmann Lab (UCSF). CRISPRi FACS screened for oxidized lipids in human iPSC-derived glutamatergic neurons. (Glutamatergic Neuron-Liperfluo-CRISPRi). The screens indicate positive hits for both ROS and lipid peroxidation in WDR45
Summary of CRISPRIBRAIN.ORG findings:
While the direct consequences of the WDR45 mutations causative of BPAN will undoubtedly require further study and clinical support, the research at present supports evidence of ferroptosis, iron-dependent ROS that leads to cell abnormalities due to intense membrane lipid peroxidation and the occurrence of oxidative stress, impaired autophagy machinery in autophagosome elongation and formation and increased cellular iron levels accompanied by mitochondrial abnormalities and diminished lysosomal function.
Interestingly, the study also found that:
Loss of prosaposin disrupts glycosphingolipid degradation, leads to lipofuscin formation, iron accumulation and impaired autophagy
Disruption of lipid metabolism, in particular glycosphingolipid degradation in the lysosome, by loss of prosaposin (PSAP), drives the formation of lipofuscin in neurons, which leads to iron accumulation and strongly induces ROS production, oxidizing lipids and leading to neuronal ferroptosis under oxidative stress.
Result suggests a direct pathogenic role of lipofuscin in inducing neuronal ferroptosis. The accumulation of lipofuscin is a pathological hallmark of many degenerative diseases, such as neuronal ceroid lipofuscinosis and inherited age-related macular degenerations114,115. It has also been characterized in Alzheimer’s disease116,117, Parkinson’s disease118, Hungtinton’s disease119,120 and GRN-associated frontotemporal dementia (FTD)
Findings suggest that inhibiting lipofuscin formation or subsequent ferroptosis may serve as new therapeutic strategies for these diseases.
Future studies on a cross-section of BPAN patient derived cells may help confirm these finding and provide a treatment path for development.
For now, patients can become active participants by providing biological samples for use in ongoing global research. Well screened, catalogued and most importantly, accessible samples that are easily and safely available are key expediting research.
LEARN HOW YOU CAN ACTIVELY SUPPORT RESEARCH by submitting biological samples (blood, primary fibroblasts, iPSC lines ) to the NIGMS Human Genetic Cell Repository, sponsored by the National Institute of General Medical Sciences, which provides scientists around the world with resources for cell and genetic research.