Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients
Abstract
:1. Introduction
2. Results
2.1. Clinical Data
2.2. Cerebrospinal Fluid Proteomics Profiles
2.3. Principal Component Analysis and Hierarchical Clustering
2.4. REVIGO Analysis on Biological Process GO-Terms Annotating Identified Proteins of Interest
2.5. Western Blot Profiles of APOE, APOA1 and Transthyretin in CSF Samples from SMA Type 1 Patients (T0 and T1) and Control Subjects
2.6. Oxidized Protein Pattern in Two SMA Type 1 Patients before and after Nusinersen Therapy
3. Discussion
3.1. Are APOE and APOA1 Crucial Allies of Nusinersen in Restoring Nervous System Plasticity in SMA Type 1 Patients?
3.2. APOE, APOA1 and Haptoglobin May Support Nusinersen in Inflammation and Oxidative Stress Balancing
3.3. Nusinersen Treatment Highly Influences Transthyretin Pattern in the Investigated Cohort of SMA Type 1 Patients
3.4. Concluding Remarks
4. Materials and Methods
4.1. Participants and Cerebrospinal Fluid Sampling
4.2. Cerebrospinal Fluid Preparation for Proteomics Analysis
4.3. Two-Dimensional Gel Electrophoresis
4.4. Image Analysis and Statistics
4.5. Mass Spectrometry by MALDI-TOF
4.6. Gene Ontology (GO) Clustering
4.7. Western Blot
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Pts a | Sex M/F | Age at Symptoms Onset (Months) | Age at Treatment Onset (Months) | CHOP INTEND T0 | CHOP INTEND T1 | ΔCHOP INTEND (T1-T0) | SMN2 Copy Number | SMA Type 1 Decimal System b | SMA Type 1 ABC System c | Respiratory Support d T0 (Hours) | Nutritional SUPPORT e T0 | Respiratory Support d T1 (Hours) | Nutritional Support e T1 | Sample T0 | Sample T1 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Pt. 1 | M | 0 | 2 | 21 | 35 | 14 | 2 | 1.5 | A | NIV (12) | None | NIV (18) | NGT | AT0 | AT1 |
Pt. 2 | M | 3 | 17 | 22 | 35 | 13 | 3 | 1.5 | B | Nocturnal NIV (8) | PEG | Nocturnal NIV (8) | PEG | BT0 | BT1 |
Pt. 3 | M | 5 | 25 | 43 | 46 | 3 | 3 | 1.9 | C | Nocturnal NIV (8) | None | Nocturnal NIV (8) | None | CT0 | CT1 |
Pt. 4 | M | 5 | 28 | 42 | 47 | 5 | 3 | 1.9 | C | None | None | None | None | DT0 | DT1 |
Pt. 5 | F | 4 | 7 | 39 | 48 | 9 | 2 | 1.9 | C | Nocturnal NIV (8) | None | Nocturnal NIV (8) | None | ET0 | ET1 |
Pt. 6 | F | 3 | 5 | 24 | 35 | 11 | 2 | 1.5 | B | Nocturnal NIV (8) | PEG | Nocturnal NIV (8) | PEG | FT0 | FT1 |
Pt. 7 | M | 2 | 3 | 30 | 48 | 18 | 2 | 1.5 | B | Nocturnal NIV (6) | None | Nocturnal NIV (4) | None | GT0 | GT1 |
Pt. 8 | M | 2 | 3 | 23 | 36 | 13 | 2 | 1.5 | B | Nocturnal NIV (8) | PEG | Nocturnal NIV (8) | PEG | HT0 | HT1 |
Pt. 9 | M | 0 | 2 | 16 | 36 | 10 | 2 | 1.1 | A | NIV (24) | PEG | NIV (24) | PEG | IT0 | IT1 |
Pt. 10 | M | 1 | 3 | 9 | 35 | 16 | 2 | 1.5 | A | NIV (10) | OGT | NIV (18) | PEG | JT0 | JT1 |
Spot N. a | Protein Description b | Ctrl Spot Mean % Vol ± SD c | T0 Spot Mean % Vol ± SD c | T1 Spot Mean % Vol ± SD c | AC d | Experimental pI; Mw e | Theoretical pI; Mw f | Mascot Search Results g | ||
---|---|---|---|---|---|---|---|---|---|---|
Score | No. of Matched Peptides | Sequence Coverage (%) | ||||||||
31 | Apolipoprotein A1 | 174 ± 46 # | 73 ± 19 # | 102 ± 38 | P02647 | 5.22; 24559 | 5.56; 30777 | 181 | 24 | 61 |
33 | Apolipoprotein A1 | 238 ± 63 # | 114 ± 48 # § | 234 ± 43 § | P02647 | 5.34; 24211 | 5.56; 30777 | 170 | 21 | 56 |
17 | Apolipoprotein E | 120 ± 49 # * | 257 ± 106 # | 254 ± 148 * | P02649 | 5.49; 36422 | 5.65; 36154 | 111 | 18 | 45 |
19 | Apolipoprotein E | 506 ± 191 # * | 214 ± 149 # | 242 ± 128 * | P02649 | 5.52; 34722 | 5.65; 36154 | 82 | 13 | 29 |
34 | Hemoglobin sub. β | 376 ± 163 | 566 ± 42 § | 213 ± 107 § # | P68871 | 6.31; 24629 | 6.74; 15998 | 99 | 12 | 82 |
35 | Hemoglobin sub. β | 462 ± 294 * | 0 | 210 ± 179 * | P68871 | 6.46; 24629 | 6.74; 15998 | 56 | 6 | 39 |
36 | Hemoglobin sub. β | 72 ± 50 | 0 | 139 ± 88 | P68871 | 7.65; 24073 | 6.74; 15998 | 83 | 8 | 62 |
49 | Hemoglobin sub. β | 123 ± 141 # | 1284 ± 1151 # | 928 ± 983 | P68871 | 6.75; 12024 | 6.74; 15998 | 100 | 10 | 80 |
50 | Mix: Hemoglobin sub. β Hemoglobin sub. α | 57 ± 30 | 0 | 0 | P68871 P69905 | 7.55; 12589 | 6.74; 15998 8.72; 15257 | 119 58 | 12 6 | 82 42 |
51 | Hemoglobin sub. α | 91 ± 79 # * | 522 ± 128 # | 485 ± 260 * | P69905 | 7.95; 12589 | 8.72; 15257 | 100 | 9 | 50 |
53 | Hemoglobin sub. α | 46 ± 52 # * | 294 ± 103 # | 565 ± 303 * | P69905 | 8.42; 12686 | 8.72; 15257 | 104 | 9 | 50 |
54 | Hemoglobin sub. α | 93 ± 31 * | 172 ± 111 | 254 ± 214 * | P69906 | 7.55; 12116 | 8.72; 15257 | 70 | 7 | 50 |
16 | Haptoglobin | 152 ± 96 | 185 ± 102 § | 44 ± 37 § | P00738 | 5.49; 41071 | 6.13; 45205 | 54 | 11 | 25 |
20 | Transthyretin | 278 ± 331 # | 15 ± 14 # § | 116 ± 82 § | P02766 | 5.39; 30717 | 5.49; 15887 | 67 | 8 | 65 |
43 | Transthyretin | 533 ± 203 # * | 129 ± 60 # § | 263 ± 137 * § | P02766 | 5.17; 14121 | 5.49; 15887 | 70 | 8 | 50 |
46 | Transthyretin | 145 ± 49 * | 227 ± 87 | 315 ± 143 * | P02766 | 5.54; 12816 | 5.49; 15887 | 116 | 10 | 65 |
48 | Transthyretin | 19 ± 12 * | 27 ± 16 | 54 ± 37 * | P02766 | 5.52; 11902 | 5.49; 15887 | 95 | 10 | 65 |
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Bianchi, L.; Sframeli, M.; Vantaggiato, L.; Vita, G.L.; Ciranni, A.; Polito, F.; Oteri, R.; Gitto, E.; Di Giuseppe, F.; Angelucci, S.; et al. Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients. Int. J. Mol. Sci. 2021, 22, 4329. https://doi.org/10.3390/ijms22094329
Bianchi L, Sframeli M, Vantaggiato L, Vita GL, Ciranni A, Polito F, Oteri R, Gitto E, Di Giuseppe F, Angelucci S, et al. Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients. International Journal of Molecular Sciences. 2021; 22(9):4329. https://doi.org/10.3390/ijms22094329
Chicago/Turabian StyleBianchi, Laura, Maria Sframeli, Lorenza Vantaggiato, Gian Luca Vita, Annamaria Ciranni, Francesca Polito, Rosaria Oteri, Eloisa Gitto, Fabrizio Di Giuseppe, Stefania Angelucci, and et al. 2021. "Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients" International Journal of Molecular Sciences 22, no. 9: 4329. https://doi.org/10.3390/ijms22094329