Proteomic Profiling Towards a Better Understanding of Genetic Based Muscular Diseases: The Current Picture and a Look to the Future

Biomolecules, Год журнала: 2025, Номер 15(1), С. 130 - 130

Опубликована: Янв. 15, 2025

Proteomics accelerates diagnosis and research of muscular diseases by enabling the robust analysis proteins relevant for manifestation neuromuscular in following aspects: (i) evaluation effect genetic variants on corresponding protein, (ii) prediction underlying defect based proteomic signature muscle biopsies, (iii) pathophysiologies different entities diseases, key definition new intervention concepts, (iv) patient stratification according to biochemical fingerprints as well (v) monitoring success therapeutic interventions. This review presents—also through exemplary case studies—the various advantages mass proteomics investigation discusses technical limitations, provides an outlook possible future application concepts. Hence, is excellent large-scale analytical tool diagnostic workup (hereditary) warrants systematic profiling pathophysiological processes. The steady development may allow overcome existing limitations including a quenched dynamic range quantification protein isoforms. Future directions include targeted settings using not only biopsies but also liquid address need minimally invasive procedures.

Язык: Английский

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Impact of Nusinersen on Neurofilament, Creatinine Levels, and Motor Function in Pediatric Spinal Muscular Atrophy Rehabilitation: A Biomarker Analysis

Balneo and PRM Research Journal, Год журнала: 2024, Номер 15(Vol.15, no. 2), С. 681 - 681

Опубликована: Июнь 21, 2024

Background: Spinal amyotrophy is a rare, neurodegenerative disease, with progressive evolution, disabling until death in severe forms, but for which 3 disease-modifying drugs have recently been approved (in the last 8 years). In this context, it became necessary to find predictive factors evolution of patients and effectiveness treatment applied personalize therapy obtain best results according particularities each patient. Objective: The objective retrospective study analyze different clinical (motor functional scales) paraclinical biomarkers (level pNF-H neurofilaments serum cerebrospinal fluid creatinine) under nusinersen various types spinal muscular atrophy (SMA). Methods: We analyzed values group 69 pediatric diagnosed SMA stages over three years, depending on type SMA, number copies SMN2 gene, age at initiation therapy. Results: observed significant increases levels both (CSF) serum, correlations symptom onset an inverse relationship gene. These decreased during nusinersen, coinciding increased creatinine improved motor assessment scores. most pronounced effects were noted forms such as 1, mainly when was initiated younger age. Conclusion: treatments should be specific scales, well against neuronal degradation: pNF-H, present CSF creatinine, marker muscle activity. Administering promptly after diagnostic confirmation halts neural degradation enhances patient's function. Keywords: atrophy; neurofilaments; fluid; biomarkers; nusinersen; creatinine;

Язык: Английский

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Multi-omics profiling of CSF from spinal muscular atrophy type 3 patients after nusinersen treatment: a 2-year follow-up multicenter retrospective study

Cellular and Molecular Life Sciences, Год журнала: 2023, Номер 80(8)

Опубликована: Авг. 1, 2023

Abstract Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene resulting reduced levels of SMN protein. Nusinersen, first antisense oligonucleotide (ASO) approved for SMA treatment, binds to SMN2 gene, paralogue , and mediates translation functional Here, we used longitudinal high-resolution mass spectrometry (MS) assess both global proteome metabolome cerebrospinal fluid (CSF) from ten type 3 patients, with aim identifying novel readouts pharmacodynamic/response treatment predictive markers response. Patients had median age 33.5 [29.5; 38.25] years, 80% them were ambulant at time enrolment, HFMSE score 37.5 [25.75; 50.75]. Untargeted CSF measured using MS (nLC-HRMS) on samples obtained before (T0) after 2 years follow-up (T22). A total 26 proteins found be differentially expressed between T0 T22 upon VSN normalization LIMMA differential analysis, accounting paired replica. Notably, key insulin-growth factor signaling pathway upregulated together selective modulation transcription regulators. Using CombiROC multimarker signature suggest that detecting reduction SEMA6A an increase COL1A2 GRIA4 might reflect therapeutic efficacy nusinersen. Longitudinal profiling, analyzed t -Test, showed significant shift some aminoacid utilization induced whereas other metabolites largely unchanged. Together, these data perturbation nusinersen still sustained 22 months confirm utility multi-omic profiling as pharmacodynamic biomarker 3. Nonetheless, validation studies are needed this evidence larger sample size further dissect combined response treatment.

Язык: Английский

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Multi-omics profiling in spinal muscular atrophy (SMA): investigating lipid and metabolic alterations through longitudinal CSF analysis of Nusinersen-treated patients

Journal of Neurology, Год журнала: 2025, Номер 272(3)

Опубликована: Фев. 4, 2025

Abstract Spinal muscular atrophy (SMA) is a rare neuromuscular disease caused by biallelic mutations in the SMN1 gene, leading to progressive muscle weakness due degeneration of anterior horn cells. Since 2017, SMA patients can be treated with anti-sense oligonucleotide Nusinersen, which promotes alternative splicing SMN2 regular intrathecal injections. In this prospective study, we applied metabolomic, lipidomic, and proteomic analysis examine sequential CSF samples from 13 controls. This multi-omic approach identified over 800 proteins 400 small molecules including lipids. Multivariate data successfully discriminated between derived control subjects. Lipidomic revealed increased levels cholesteryl esters lyso-phospholipids, along reduced cholesterol phospholipids as compared healthy These data, combined results functional assays, led us conclude that exhibit altered function high-density-lipoprotein (HDL)-like particles CSF. Notably, Nusinersen therapy was observed reverse disease-specific profile changes toward physiological state, potentially explicable restoring HDL function.

Язык: Английский

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Biomarker Evolution in Pediatric SMA: Insights from CSF pNF-H Dynamics and SMN2 Copy Number During Nusinersen Therapy

Balneo and PRM Research Journal, Год журнала: 2025, Номер 16(Vol 16 No. 1), С. 777 - 777

Опубликована: Март 31, 2025

Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder caused by insufficient survival motor neuron (SMN) protein synthesis, leading to progressive loss and debilitating symptoms. This study evaluates cerebrospinal fluid (CSF) phosphorylated neurofilament-heavy chain (pNF-H) levels as predictive markers of function in 73 pediatric SMA patients undergoing nusinersen treatment. pNF-H, structural component neurons, released into the CSF serum during neuronal damage or degeneration. aims address this gap assessing pNF-H dynamics relation changes over course It examines evolution different time periods initial clinical biological parameters their progression at start treatment response therapy. Patients were stratified SMN2 gene copy number, which modulates disease severity inversely correlated with higher indicating more neurodegeneration. also function, baseline linked lower scores. During treatment, declined alongside improvements, supporting its role longitudinal biomarker. In 2 copies, larger early variations predicted better gains 1 years, while smaller maintenance improvement. 3 fluctuations associated scores, along creatinine years. Longitudinal analyses revealed that sustained decreases enhanced outcomes. The highlights level robust predictor efficacy, offering insights therapeutic impact. These findings underscore critical intervention personalized biomarker monitoring optimizing quality life for patients.

Язык: Английский

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Insights into spinal muscular atrophy from molecular biomarkers

Neural Regeneration Research, Год журнала: 2024, Номер 20(7), С. 1849 - 1863

Опубликована: Июнь 26, 2024

Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness. It one the most common genetic causes mortality among infants aged less than 2 years. Biomarker research currently receiving more attention, and new candidate biomarkers are constantly being discovered. This review initially discusses evaluation methods commonly used in clinical practice while briefly outlining their respective pros cons. We also describe recent advancements significance molecular for spinal atrophy, which classified as either specific or non-specific biomarkers. provides insights into pathogenesis mechanism response to drug-modified therapies, selection biomarker candidates, would promote development future research. Furthermore, successful utilization may facilitate implementation gene-targeting treatments patients with atrophy.

Язык: Английский

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SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Ноя. 13, 2023

Beyond motor neuron degeneration, homozygous mutations in the survival 1 (SMN1) gene cause multiorgan and metabolic defects patients with spinal muscular atrophy (SMA). However, precise biochemical features of these alterations age onset brain peripheral organs remain unclear. Using untargeted NMR-based metabolomics SMA mice, we identify cerebral hepatic abnormalities related to energy homeostasis pathways amino acid metabolism, emerging already at postnatal day 3 (P3) liver. Through HPLC, find that SMN deficiency induces a drop norepinephrine levels overt symptomatic mice P11, affecting mRNA protein expression key genes regulating monoamine including aromatic L-amino decarboxylase (AADC), dopamine beta-hydroxylase (DβH) oxidase A (MAO-A). In support translational value our preclinical observations, also discovered upregulation increases cerebrospinal fluid concentration Nusinersen-treated SMA1 patients. Our findings highlight previously unrecognized harmful influence low on critical enzymes involved suggesting SMN-inducing therapies may modulate catecholamine neurotransmission. These results be relevant for setting therapeutic approaches counteract SMA.

Язык: Английский

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Metabolomics of cerebrospinal fluid reveals candidate diagnostic biomarkers to distinguish between spinal muscular atrophy type II and type III

CNS Neuroscience & Therapeutics, Год журнала: 2024, Номер 30(4)

Опубликована: Апрель 1, 2024

Abstract Aims Classification of spinal muscular atrophy (SMA) is associated with the clinical prognosis; however, objective classification markers are scarce. This study aimed to identify metabolic in cerebrospinal fluid (CSF) children SMA types II and III. Methods CSF samples were collected from 40 patients (27 type 13 III) analyzed for metabolites. Results We identified 135 metabolites These lysine degradation arginine, proline, tyrosine metabolism. seven Hammersmith Functional Motor Scale: 4‐chlorophenylacetic acid, adb‐chminaca,(+/−)‐, dodecyl benzenesulfonic norethindrone acetate, 4‐(undecan‐5‐yl) benzene‐1‐sulfonic dihydromaleimide beta‐d‐glucoside, cinobufagin. Potential typing biomarkers, N‐cyclohexylformamide, cinobufagin, cotinine glucuronide, N‐myristoyl geranic benzene, 7,8‐diamino pelargonate, showed good predictive performance. Among these, arginine was unaffected by gene phenotype. Conclusion promising candidate prognostic factors SMA. also pathways severity assessments can help predict outcomes screening biomarkers.

Язык: Английский

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Cerebrospinal Fluid Proteomic Changes after Nusinersen in Patients with Spinal Muscular Atrophy

Journal of Clinical Medicine, Год журнала: 2023, Номер 12(20), С. 6696 - 6696

Опубликована: Окт. 23, 2023

Disease-modifying treatments have transformed the natural history of spinal muscular atrophy (SMA), but cellular pathways altered by SMN restoration remain undefined and biomarkers cannot yet precisely predict treatment response. We performed an exploratory cerebrospinal fluid (CSF) proteomic study in a diverse sample SMA patients treated with nusinersen to elucidate therapeutic identify predictors motor improvement. Proteomic analyses were on CSF samples collected before (T0) at 6 months (T6) using Olink panel quantify 1113 peptides. A supervised machine learning approach was used proteins that discriminated who improved functionally from those did not after 2 years treatment. total 49 included (10 type 1, 18 2, 21 3), ranging age 3 65 years. Most showed decrease concentration T6. The algorithm identified ARSB, ENTPD2, NEFL, IFI30 as most predictive model able improvement 79.6% accuracy. results highlight potential application following Validation larger datasets is needed.

Язык: Английский

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Proteomics profiling and machine learning in nusinersen-treated patients with spinal muscular atrophy

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Сен. 10, 2024

Язык: Английский

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