Novel Target for the Suppression of Degenerative Disease

Penn State University Background
Autophagy is a critical cell process that protects cells from a variety of stressors, removing damaged proteins and organelles. Activation of autophagy is also associated with mitochondrial repair and their increased capacity to catabolize lipids. Basal levels of autophagy affect lifespan and loss or down-regulation of autophagy lead to cell death. The disruption of autophagy is pronounced in neurodegenerative disorders characterized by the accumulation of toxic protein aggregates, intracellular lipids, and dysfunctional mitochondria.
Technology Overview
Heparan sulfate (HS) proteoglycans are abundant carbohydrate-modified proteins found on cell surfaces and in the extracellular matrix. This class of proteins serves important roles in processes at the cell surface, including growth factor signaling and endocytosis of several ligands, including lipoproteins. HS assembly requires several enzymes, and Penn State researchers have characterized one critical component of that machinery, N-deacetylase N-sulfotransferase (NDST1). Compromising the NDST1 function lowers the sulfation state of HS and affects several important events central to neurodegeneration. In particular, lowering NDST1 function increases autophagy flux, results in expansion of the mitochondrial network, and produces cells with elevated levels of oxidative metabolism. Evidence suggests this is mediated by compromising HS‑modified protein co-receptor function in the regulation of MAP kinase and ERK1,2 signaling. Inhibition of NDST1 results in resistance to ROS stress, lowered intracellular lipid levels, and suppression of cell degeneration in Drosophila models of Alzheimer’s and Parkinson’s diseases. Ameliorative effects on cell health do not require complete knockdown of NDST1 activity; a remarkably 50% reduction in mRNA levels and a 15% change in HS sulfation state is sufficient to observe rescue of neurodegenerative phenotypes.
These results support the concept that modulation of NDST1 represents a valuable target that can be exploited to suppress or treat degenerative diseases, especially those associated with the accumulation of aggregated proteins, damaged mitochondria, and intracellular lipids in the CNS or other tissue types.
Further Details
unpublished results available upon request
Stage of Development
Research is ongoing. Penn State researchers are working with collaborators to develop an initial suite of small molecule inhibitors hits, confirm results in vivo (mouse), and select a primary therapeutic indication. Based on early research results, Penn State researchers believe that anti-sense oligos may also represent an effective inhibitor modality. The researchers seek academic and/or industry partnerships as well as funding to continue development.

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