Genetic analysis of the X-linked Adrenoleukodystrophy ABCD1 gene in Drosophila uncovers a role in Peroxisomal dynamics

作者：Joshua Manor, Sharayu Jangam, Hyung-Lok Chung, Pranjali Bhagwat, Jonathan Andrews, Hillary Chester, Shu Kondo, Saurabh Kumar Srivastav, Juan Botas, Ann B. Moser, Suzette M Huguenin, Michael F. Wangler · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.09.23.614586 · 被引用次数：2 · 研究领域：Peroxisome Proliferator-Activated Receptors、Adipose Tissue and Metabolism、Lipid metabolism and biosynthesis

ABSTRACT X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder caused by a loss-of-function (LOF) mutation in the ATP-binding cassette subfamily D member 1 ( ABCD1) gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). This disorder exhibits striking heterogeneity; some male patients develop an early childhood neuroinflammatory demyelination disorder, while other patients, including adult males and most affected female carriers, experience a chronic progressive myelopathy. Adrenocortical failure is observed in almost all male patients, with age of onset varying sometimes being the first diagnostic finding. The gene underlying this spectrum of disease encodes an ATP-binding cassette (ABC) transporter that localizes to peroxisomes and facilitates VLCFA transport. X-ALD is considered a single peroxisomal component defect and does not play a direct role in peroxisome assembly. Drosophila models of other peroxisomal genes have provided mechanistic insight into some of the neurodegenerative mechanisms with reduced lifespan, retinal degeneration, and VLCFA accumulation. Here, we perform a genetic analysis of the fly ABCD1 ortholog Abcd1 (CG2316). Knockdown or deficiency of Abcd1 leads to VLCFA accumulation, salivary gland defects, locomotor impairment and retinal lipid abnormalities. Interestingly, there is also evidence of reduced peroxisomal numbers. Flies overexpressing the human cDNA for ABCD1 display a wing crumpling phenotype ch...