Gene Expression-Related Changes in Morphologies of Organelles and Cellular Component Organization in Mucopolysaccharidoses
Mucopolysaccharidoses (MPS) are inherited metabolic diseases characterized by accumulation of incompletely degraded glycosaminoglycans (GAGs) in lysosomes. Although primary causes of these diseases are mutations in genes coding for enzymes involved in lysosomal GAG degradation, it was demonstrated t...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-03-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/5/2766 |
| _version_ | 1797542034912837632 |
|---|---|
| author | Lidia Gaffke Karolina Pierzynowska Estera Rintz Zuzanna Cyske Izabela Giecewicz Grzegorz Węgrzyn |
| author_facet | Lidia Gaffke Karolina Pierzynowska Estera Rintz Zuzanna Cyske Izabela Giecewicz Grzegorz Węgrzyn |
| author_sort | Lidia Gaffke |
| collection | DOAJ |
| description | Mucopolysaccharidoses (MPS) are inherited metabolic diseases characterized by accumulation of incompletely degraded glycosaminoglycans (GAGs) in lysosomes. Although primary causes of these diseases are mutations in genes coding for enzymes involved in lysosomal GAG degradation, it was demonstrated that storage of these complex carbohydrates provokes a cascade of secondary and tertiary changes affecting cellular functions. Potentially, this might lead to appearance of cellular disorders which could not be corrected even if the primary cause of the disease is removed. In this work, we studied changes in cellular organelles in MPS fibroblasts relative to control cells. All 11 types and subtypes of MPS were included into this study to obtain a complex picture of changes in organelles in this group of diseases. Two experimental approaches were employed, transcriptomic analyses and electron microscopic assessment of morphology of organelles. We analyzed levels of transcripts of genes grouped into two terms included into the QuickGO database, ‘Cellular component organization’ (GO:0016043) and ‘Cellular anatomical entity’ (GO:0110165), to find that number of transcripts with significantly changed levels in MPS fibroblasts vs. controls ranged from 109 to 322 (depending on MPS type) in GO:0016043, and from 70 to 208 in GO:0110165. This dysregulation of expression of genes crucial for proper structures and functions of various organelles was accompanied by severe changes in morphologies of lysosomes, nuclei, mitochondria, Golgi apparatus, and endoplasmic reticulum. Interestingly, some observed changes occurred in all/most MPS types while others were specific to particular disease types/subtypes. We suggest that severe changes in organelles in MPS cells might arise from dysregulation of expression of a battery of genes involved in organelles’ structures and functions. Intriguingly, normalization of GAG levels by using recombinant human enzymes specific to different MPS types corrected morphologies of some, but not all, organelles, while it failed to improve regulation of expression of selected genes. These results might suggest reasons for inability of enzyme replacement therapy to correct all MPS symptoms, particularly if initiated at advanced stages of the disease. |
| first_indexed | 2024-03-10T13:24:53Z |
| format | Article |
| id | doaj.art-2d3b15008a05457dbff7c923e517ecb9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:24:53Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2d3b15008a05457dbff7c923e517ecb92023-11-21T09:45:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01225276610.3390/ijms22052766Gene Expression-Related Changes in Morphologies of Organelles and Cellular Component Organization in MucopolysaccharidosesLidia Gaffke0Karolina Pierzynowska1Estera Rintz2Zuzanna Cyske3Izabela Giecewicz4Grzegorz Węgrzyn5Department of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, PolandDepartment of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, PolandDepartment of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, PolandDepartment of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, PolandDepartment of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, PolandDepartment of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, PolandMucopolysaccharidoses (MPS) are inherited metabolic diseases characterized by accumulation of incompletely degraded glycosaminoglycans (GAGs) in lysosomes. Although primary causes of these diseases are mutations in genes coding for enzymes involved in lysosomal GAG degradation, it was demonstrated that storage of these complex carbohydrates provokes a cascade of secondary and tertiary changes affecting cellular functions. Potentially, this might lead to appearance of cellular disorders which could not be corrected even if the primary cause of the disease is removed. In this work, we studied changes in cellular organelles in MPS fibroblasts relative to control cells. All 11 types and subtypes of MPS were included into this study to obtain a complex picture of changes in organelles in this group of diseases. Two experimental approaches were employed, transcriptomic analyses and electron microscopic assessment of morphology of organelles. We analyzed levels of transcripts of genes grouped into two terms included into the QuickGO database, ‘Cellular component organization’ (GO:0016043) and ‘Cellular anatomical entity’ (GO:0110165), to find that number of transcripts with significantly changed levels in MPS fibroblasts vs. controls ranged from 109 to 322 (depending on MPS type) in GO:0016043, and from 70 to 208 in GO:0110165. This dysregulation of expression of genes crucial for proper structures and functions of various organelles was accompanied by severe changes in morphologies of lysosomes, nuclei, mitochondria, Golgi apparatus, and endoplasmic reticulum. Interestingly, some observed changes occurred in all/most MPS types while others were specific to particular disease types/subtypes. We suggest that severe changes in organelles in MPS cells might arise from dysregulation of expression of a battery of genes involved in organelles’ structures and functions. Intriguingly, normalization of GAG levels by using recombinant human enzymes specific to different MPS types corrected morphologies of some, but not all, organelles, while it failed to improve regulation of expression of selected genes. These results might suggest reasons for inability of enzyme replacement therapy to correct all MPS symptoms, particularly if initiated at advanced stages of the disease.https://www.mdpi.com/1422-0067/22/5/2766mucopolysaccharidosestranscriptomic analysesorganelleselectron microscopy |
| spellingShingle | Lidia Gaffke Karolina Pierzynowska Estera Rintz Zuzanna Cyske Izabela Giecewicz Grzegorz Węgrzyn Gene Expression-Related Changes in Morphologies of Organelles and Cellular Component Organization in Mucopolysaccharidoses International Journal of Molecular Sciences mucopolysaccharidoses transcriptomic analyses organelles electron microscopy |
| title | Gene Expression-Related Changes in Morphologies of Organelles and Cellular Component Organization in Mucopolysaccharidoses |
| title_full | Gene Expression-Related Changes in Morphologies of Organelles and Cellular Component Organization in Mucopolysaccharidoses |
| title_fullStr | Gene Expression-Related Changes in Morphologies of Organelles and Cellular Component Organization in Mucopolysaccharidoses |
| title_full_unstemmed | Gene Expression-Related Changes in Morphologies of Organelles and Cellular Component Organization in Mucopolysaccharidoses |
| title_short | Gene Expression-Related Changes in Morphologies of Organelles and Cellular Component Organization in Mucopolysaccharidoses |
| title_sort | gene expression related changes in morphologies of organelles and cellular component organization in mucopolysaccharidoses |
| topic | mucopolysaccharidoses transcriptomic analyses organelles electron microscopy |
| url | https://www.mdpi.com/1422-0067/22/5/2766 |
| work_keys_str_mv | AT lidiagaffke geneexpressionrelatedchangesinmorphologiesoforganellesandcellularcomponentorganizationinmucopolysaccharidoses AT karolinapierzynowska geneexpressionrelatedchangesinmorphologiesoforganellesandcellularcomponentorganizationinmucopolysaccharidoses AT esterarintz geneexpressionrelatedchangesinmorphologiesoforganellesandcellularcomponentorganizationinmucopolysaccharidoses AT zuzannacyske geneexpressionrelatedchangesinmorphologiesoforganellesandcellularcomponentorganizationinmucopolysaccharidoses AT izabelagiecewicz geneexpressionrelatedchangesinmorphologiesoforganellesandcellularcomponentorganizationinmucopolysaccharidoses AT grzegorzwegrzyn geneexpressionrelatedchangesinmorphologiesoforganellesandcellularcomponentorganizationinmucopolysaccharidoses |