Bonkowsky Laboratory Research
Leukodystrophies Overview
Leukodystrophies are a group of rare genetic disorders that affect myelin, the protective coating around nerve fibers in the brain and nervous system. They occur in roughly 1 in 5,000 births and many forms still lack effective treatments. Because these diseases are rare, their underlying biology is not fully understood, making research critical for developing therapies.
Our lab uses cells, zebrafish and mammalian models to study leukodystrophies.
Our goal is to identify and test new drugs and gene therapies that could prevent or treat leukodystrophies and improve outcomes for affected patients and families.
Research
Vanishing White Matter
Vanishing White Matter (VWM) Disease is a rare genetic disorder that affects the brain and nervous system.
It is caused by mutations in the eIF2B complex, which is essential for healthy cell function. Changes in any of the five subunits of eIF2B can lead to VWM, resulting in loss of the protective myelin coating around nerve fibers, neurological decline, and serious health complications.
Pictured: Multi-Stained (DAPI, GFAP, GFP, NeuN) mouse hippocampus in VWM disease model.
Our lab has developed a zebrafish model of VWM disease to better understand how these mutations impact the nervous system. By creating mutations in zebrafish eIF2B genes, we observe effects on growth, survival, behavior, brain development, and nerve cell function.
Our ongoing research explores this pathway in both zebrafish and mouse models, with the goal of uncovering new insights that could guide future therapies for VWM disease.
Notably, the eif2B-2 subunit in zebrafish mirrors the function seen in humans, helping us study disease mechanisms more effectively.
We have found that eIF2B mutations trigger an activated stress response in cells even under normal conditions.
X-Linked Adrenoleukodystrophy (X-ALD)
Zebrafish (Danio rerio). AB strain. Female (top) and male (bottom). Credit: Tohru Murakami via Flickr CC BY-NC 2.0
X-ALD is a severe metabolic and neurodegenerative leukodystrophy. This disorder is caused by mutations in the ABCD1 gene, which encodes a peroxisomal transporter involved in the degradation of very long chain fatty acids (VLCFA). X-ALD is characterized by phenotypic heterogeneity, resulting in a delayed diagnosis in the absence of newborn screening and remains without any satisfying therapy or disease models.
An ABCD1 mutant zebrafish model has been developed in our lab and it phenocopies several traits found in patients; there is an accumulation of VLCFA, adrenal-like insufficiency, increased oligodendrocyte apoptosis, and reduced survival and swimming behavior.
Our work is now focusing in on characterizing the relation between the peroxisomal defect and the myelin disruption in X-ALD. Taking advantage of the zebrafish high fecundity and rapid development, we are screening drug candidates capable of improving myelin restoration in X-ALD. (We are also interested in other peroxisomal leukodystrophies and investigating the potential benefit of gene therapies for these diseases.)
Neurodegenerative diseases including Leukodystrophy with Vanishing White Matter (VWM) have activation of the integrated stress response (ISR).
Our objective is analysis of stress granules (SGs), membrane-less cytoplasmic ribonucleoprotein aggregations, which have been identified as a key mediator of ISR activation and pathophysiology.
We have found an increase in SGs and in apoptosis in the brains of zebrafish and mice with VWM; more severe mutants had larger increases in SGs and apoptosis.
Our results suggest that SGs mediate VWM disease pathophysiology, and that staufen1 acts as a feedback link between ISR activation and SG formation. Our findings suggest novel opportunities to disrupt CNS pathophysiology of VWM. Further, there may be mechanisms of neurodegeneration shared from VWM with more common adult neurodegenerative conditions.