Project Summary/Abstract
Adrenoleukodystrophy (ALD) is a hereditary metabolic disorder that manifests with inflammatory degeneration
of the brain and progressive spinal cord atrophy. ALD is characterized by an accumulation of very long chain
fatty acids (VLCFA) that are usually restricted to small amounts in healthy tissue. The buildup of VLCFAs
contributes to the development of oxidative stress injury, disrupted mitochondrial homeostasis, and other
stressors that culminate in the loss of brain myelin, the fatty sheath that insulates nerve fibers, and robust
neuroinflammation that altogether precipitate the deterioration of the major fiber tracts within the central nervous
system (CNS). Despite early detection via newborn screening, only a small fraction of patients enjoys a
therapeutic option in bone marrow transplantation, which is the sole approved therapy for ALD. For the majority
of patients, however, bone marrow transplantation is ineffective, particularly for the spinal cord atrophy
phenotype which has near complete penetrance. Approaches to broaden therapeutic options are critical then,
and especially relevant is the discovery of molecular targets and pathways that can help reverse the disease
processes. We found that one candidate target is the nuclear receptor called peroxisome proliferator activated
receptor beta/delta (Pparß/d), which serves as a regulator for various lipid metabolic pathways in the brain cell-
type that produces myelin and is critical for myelin maintenance. We have observed that genes regulated by
Pparß/d encode key components necessary for VLCFA metabolism, which when upregulated can compensate
for the VLCFA oxidation defect observed in ALD. In this proposal, we will work to elucidate the role of Pparß/d
in the context of ALD, with the aims of determining the mechanism by which Pparß/d can mitigate the
accumulation of VLCFAs in disease relevant tissues. Additionally, this project will reveal novel molecular
pathways underlying the pathomechanism of ALD, which will amplify pursuable therapeutic targets, as well as
decipher how disruptions in the immune compartment can aggravate disease progression. To accomplish these
aims, the project will employ genetically engineered mice and various primary cell culture systems as model
systems for ALD, along with an assortment of well-established methods and rigorously designed experimental
approaches. In sum, this comprehensive study will help delineate a targetable molecular pathway with
therapeutic potential for ALD, as well as describe additional molecular pathways pertinent to disease onset and
progression. Additionally, this project will also provide the PI with a substantial training and learning experience
to facilitate the development into a skilled and innovative physician scientist.
