Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans
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 associate...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.1012706/full |
| _version_ | 1797957414954205184 |
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| author | Nicholas Schultheis Robert Becker Gelila Berhanu Alexander Kapral Matthew Roseman Shalini Shah Alyssa Connell Scott Selleck Scott Selleck |
| author_facet | Nicholas Schultheis Robert Becker Gelila Berhanu Alexander Kapral Matthew Roseman Shalini Shah Alyssa Connell Scott Selleck Scott Selleck |
| author_sort | Nicholas Schultheis |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T00:03:46Z |
| format | Article |
| id | doaj.art-d6c8495f1b0c4e1bbecf49a28d16e240 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-11T00:03:46Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-d6c8495f1b0c4e1bbecf49a28d16e2402023-01-09T14:49:27ZengFrontiers Media S.A.Frontiers in Genetics1664-80212023-01-011310.3389/fgene.2022.10127061012706Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycansNicholas Schultheis0Robert Becker1Gelila Berhanu2Alexander Kapral3Matthew Roseman4Shalini Shah5Alyssa Connell6Scott Selleck7Scott Selleck8Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United StatesDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United StatesDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United StatesDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United StatesDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United StatesDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United StatesDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United StatesDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United StatesDepartment of Biochemistry and Microbiology, University of Victoria, Victoria, BC, CanadaHeparan 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.https://www.frontiersin.org/articles/10.3389/fgene.2022.1012706/fullautophagylipid metabolismmitochondriaheparan sulfateproteoglycanspresenilin |
| spellingShingle | Nicholas Schultheis Robert Becker Gelila Berhanu Alexander Kapral Matthew Roseman Shalini Shah Alyssa Connell Scott Selleck Scott Selleck Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans Frontiers in Genetics autophagy lipid metabolism mitochondria heparan sulfate proteoglycans presenilin |
| title | Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans |
| title_full | Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans |
| title_fullStr | Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans |
| title_full_unstemmed | Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans |
| title_short | Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans |
| title_sort | regulation of autophagy lipid metabolism and neurodegenerative pathology by heparan sulfate proteoglycans |
| topic | autophagy lipid metabolism mitochondria heparan sulfate proteoglycans presenilin |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.1012706/full |
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