Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the <i>FMR1</i> premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/17/13477 |
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| author | Marwa Zafarullah Jie Li Michelle R. Salemi Brett S. Phinney Blythe P. Durbin-Johnson Randi Hagerman David Hessl Susan M. Rivera Flora Tassone |
| author_facet | Marwa Zafarullah Jie Li Michelle R. Salemi Brett S. Phinney Blythe P. Durbin-Johnson Randi Hagerman David Hessl Susan M. Rivera Flora Tassone |
| author_sort | Marwa Zafarullah |
| collection | DOAJ |
| description | Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the <i>FMR1</i> premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS. |
| first_indexed | 2024-03-10T23:21:56Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:21:56Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d7c20dccf5c1447c9320f6edd25352052023-11-19T08:17:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124171347710.3390/ijms241713477Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTASMarwa Zafarullah0Jie Li1Michelle R. Salemi2Brett S. Phinney3Blythe P. Durbin-Johnson4Randi Hagerman5David Hessl6Susan M. Rivera7Flora Tassone8Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USAGenome Center, Bioinformatics Core, University of California Davis, Davis, CA 95616, USAGenome Center, Proteomics Core, Genome and Biomedical Sciences Facility, University of California Davis, Davis, CA 95616, USAGenome Center, Proteomics Core, Genome and Biomedical Sciences Facility, University of California Davis, Davis, CA 95616, USADivision of Biostatistics, School of Medicine, University of California Davis, Davis, CA 95616, USAMIND Institute, University of California Davis Medical Center, Sacramento, CA 95817, USAMIND Institute, University of California Davis Medical Center, Sacramento, CA 95817, USAMIND Institute, University of California Davis Medical Center, Sacramento, CA 95817, USADepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USAFragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the <i>FMR1</i> premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS.https://www.mdpi.com/1422-0067/24/17/13477fragile X-associated tremor/ataxia syndromeFXTASpremutationblood proteomicbiomarkerprotein alterations |
| spellingShingle | Marwa Zafarullah Jie Li Michelle R. Salemi Brett S. Phinney Blythe P. Durbin-Johnson Randi Hagerman David Hessl Susan M. Rivera Flora Tassone Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS International Journal of Molecular Sciences fragile X-associated tremor/ataxia syndrome FXTAS premutation blood proteomic biomarker protein alterations |
| title | Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS |
| title_full | Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS |
| title_fullStr | Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS |
| title_full_unstemmed | Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS |
| title_short | Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS |
| title_sort | blood proteome profiling reveals biomarkers and pathway alterations in fragile x pm at risk for developing fxtas |
| topic | fragile X-associated tremor/ataxia syndrome FXTAS premutation blood proteomic biomarker protein alterations |
| url | https://www.mdpi.com/1422-0067/24/17/13477 |
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