Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans

Abstract

Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor functions in the regulation of signaling as well as membrane trafficking. Many of these activities directly affect processes associated with neurodegeneration including uptake and export of Tau protein, disposition of Amyloid Precursor Protein-derived peptides, and regulation of autophagy. In this review we focus on the impact of HSPGs on autophagy, membrane trafficking, mitochondrial quality control and biogenesis, and lipid metabolism. Disruption of these processes are a hallmark of Alzheimer’s disease (AD) and there is evidence that altering heparan sulfate structure and function could counter AD-associated pathological processes. Compromising presenilin function in several systems has provided instructive models for understanding the molecular and cellular underpinnings of AD. Disrupting presenilin function produces a constellation of cellular deficits including accumulation of lipid, disruption of autophagosome to lysosome traffic and reduction in mitochondrial size and number. Inhibition of heparan sulfate biosynthesis has opposing effects on all these cellular phenotypes, increasing mitochondrial size, stimulating autophagy flux to lysosomes, and reducing the level of intracellular lipid. These findings suggest a potential mechanism for countering pathology found in AD and related disorders by altering heparan sulfate structure and influencing cellular processes disrupted broadly in neurodegenerative disease. Vertebrate and invertebrate model systems, where the cellular machinery of autophagy and lipid metabolism are conserved, continue to provide important translational guideposts for designing interventions that address the root cause of neurodegenerative pathology.

Heparan sulfate modified proteins affect cellular processes central to neurodegeneration and modulatepresenilinfunction

“…A number of findings over the years have implicated heparan sulfate modified proteins in AD pathogenesis 15,63 . Recently, a dramatic example was reported for a member of a large kindred with a dominant disease-causing mutation in PSEN1 11 .…”

“…HSPGs are known to affect signaling via PI3kinase, Akt, and MAPK systems 13,14 . HSPGs regulate Wnt, Hh, FGF, and BMP signaling during development and play a role in both endocytosis and exocytosis of a variety of molecules [15][16][17][18] .…”

Global impact of proteoglycan science on human diseases

“…Numerous genetic studies have clearly shown an important role for glypicans in developmental morphogenesis and patterning events. 39 , 40 In vivo evidence indicates that the main function of membrane-attached glypicans is to act as growth factor co-receptors including Wnt signaling (see previous text), Hedgehogs ( Hh ), vascular and fibroblast growth factors (VEGFA and FGF2), and bone morphogenetic proteins (BMPs). Glypicans have been implicated in the pathogenesis of several types of cancer, notably hepatocellular carcinomas, and as potential biomarkers and potential targets for personalized therapy.…”

The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

“…Several excellent reviews on extracellular and cell surface HS–PGs exist in the literature. The interested reader is referred to these for further information [ 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 ]. In this review, the more important aspects of HS interactive components with representative examples of HS–PGs, such as perlecan and the syndecan, will be covered.…”