{"id":{"repo_id":"milano","oai_identifier":"oai:air.unimi.it:2434/1201933"},"canonical_url":"https://search.dev.ndltd.org/etd/milano/oai:air.unimi.it:2434/1201933","repository":{"repo_id":"milano","name":"Università degli Studi di Milano","base_url":"https://air.unimi.it/oai/request"},"display":{"title":"SMN DEFICIENCY INDUCES NEUROACTIVE AMINOACIDS DYSMETABOLISM: BRIDGING INSIGHTS FROM PRECLINICAL MODELS TO CLINICAL EVIDENCE IN SMA PATIENTS","abstract":"ABSTRACT Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, driven by homozygous loss of the SMN1 gene and reduced SMN protein. Although disease-modifying therapies such as Nusinersen, Risdiplam, and Onasemnogene abeparvovec have markedly improved survival and motor outcomes, they are not curative, and many patients continue to exhibit residual weakness, metabolic instability, and heterogeneous responses. This underscores the need for SMN-independent therapeutic strategies and robust biomarkers to enable personalised disease management. We investigated how SMN deficiency disrupts amino acid metabolism and neurotransmission across central and peripheral systems, integrating data from SMA mouse models, Drosophila, and patient biofluids. First, we show that excitatory amino acids, including L-glutamate, L-glutamine, D-serine, and D-aspartate, are dysregulated in the CNS and cerebrospinal fluid (CSF) of SMA, compromising glutamatergic neurotransmission—supplementation with D-serine improved motor performance in severe SMA mice, identifying a tractable metabolic target. Second, we discovered a selective deficiency of L-arginine in the spinal cord of SMA mice and in CSF from SMA1 patients, which Nusinersen restored in severe cases. Given L-arginine’s dual role in nitric oxide signalling and nitrogen/energy metabolism, this finding links SMN loss to both synaptic and vascular dysfunction. Third, we identified taurine deficiency in the SMA mice brainstem and CSF of patients, also corrected by Nusinersen in SMA1, nominating an additional candidate for adjunctive therapy. Extending beyond the CNS, systematic profiling in SmnΔ7 mice revealed widespread depletion of L-arginine and L-alanine across skeletal muscle, liver, kidney, and serum, alongside elevated glutamine/glutamate ratios, a systemic signature conserved in Drosophila SMA models. These metabolic changes were accompanied by stereospecific imbalances in D/L amino acids, as well as DNA damage and innate immune activation, establishing links between SMN loss, metabolic stress, and genome instability. Collectively, these studies establish amino acid dysregulation spanning central, peripheral, and stereospecific dimensions as a conserved hallmark of SMA. By integrating cross-species evidence, they highlight amino acids as grounded therapeutic candidates for SMN-independent intervention. This work provides a translational framework for developing biomarker-guided combination strategies to improve long-term outcomes in SMA.","abstract_html":"ABSTRACT Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, driven by homozygous loss of the SMN1 gene and reduced SMN protein. Although disease-modifying therapies such as Nusinersen, Risdiplam, and Onasemnogene abeparvovec have markedly improved survival and motor outcomes, they are not curative, and many patients continue to exhibit residual weakness, metabolic instability, and heterogeneous responses. This underscores the need for SMN-independent therapeutic strategies and robust biomarkers to enable personalised disease management. We investigated how SMN deficiency disrupts amino acid metabolism and neurotransmission across central and peripheral systems, integrating data from SMA mouse models, Drosophila, and patient biofluids. First, we show that excitatory amino acids, including L-glutamate, L-glutamine, D-serine, and D-aspartate, are dysregulated in the CNS and cerebrospinal fluid (CSF) of SMA, compromising glutamatergic neurotransmission—supplementation with D-serine improved motor performance in severe SMA mice, identifying a tractable metabolic target. Second, we discovered a selective deficiency of L-arginine in the spinal cord of SMA mice and in CSF from SMA1 patients, which Nusinersen restored in severe cases. Given L-arginine’s dual role in nitric oxide signalling and nitrogen/energy metabolism, this finding links SMN loss to both synaptic and vascular dysfunction. Third, we identified taurine deficiency in the SMA mice brainstem and CSF of patients, also corrected by Nusinersen in SMA1, nominating an additional candidate for adjunctive therapy. Extending beyond the CNS, systematic profiling in SmnΔ7 mice revealed widespread depletion of L-arginine and L-alanine across skeletal muscle, liver, kidney, and serum, alongside elevated glutamine/glutamate ratios, a systemic signature conserved in Drosophila SMA models. These metabolic changes were accompanied by stereospecific imbalances in D/L amino acids, as well as DNA damage and innate immune activation, establishing links between SMN loss, metabolic stress, and genome instability. Collectively, these studies establish amino acid dysregulation spanning central, peripheral, and stereospecific dimensions as a conserved hallmark of SMA. By integrating cross-species evidence, they highlight amino acids as grounded therapeutic candidates for SMN-independent intervention. This work provides a translational framework for developing biomarker-guided combination strategies to improve long-term outcomes in SMA.","abstract_has_math":false,"creators":["HASSAN, AMBER"],"institution":"Università degli Studi di Milano","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["supervisor: A. Usiello ; internal supervisor: F. Salvatore ; internal evaluator: E. M. Valente ; external evaluator: M. Bowerman","Bowerman","Melissa","A. Hassan"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-12-19","date_published":"2025-12-19","updated_at":"2026-07-27T20:18:48Z","subjects":["Spinal muscular atrophy (SMA)","Survival motor neuron (SMN)","Amino acid metabolism","L-arginine","L-alanine","Taurine","D-serine","Glutamine/glutamate ratio","D/L amino acid","Neuroinflammation","Cerebrospinal fluid (CSF)","Biomarker","Nusinersen","SmnΔ7 mouse model","Drosophila SMA model","Translational neuroscience","Settore BIOS-07/A - Biochimica","Settore BIOS-09/A - Biochimica clinica e biologia molecolare clinica","Settore MEDS-12/A - Neurologia","Settore MEDS-01/A - Genetica medica"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess","license:Creative commons","license uri:http://creativecommons.org/licenses/by-sa/4.0/"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["http://dx.doi.org/10.13130/hassan-amber_phd2025-12-19","10.13130/hassan-amber_phd2025-12-19"],"render_values":[{"text":"http://dx.doi.org/10.13130/hassan-amber_phd2025-12-19","href":"http://dx.doi.org/10.13130/hassan-amber_phd2025-12-19","code":true},{"text":"10.13130/hassan-amber_phd2025-12-19","href":"https://doi.org/10.13130/hassan-amber_phd2025-12-19","code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2434/1201933","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["supervisor: A. 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Although disease-modifying therapies such as Nusinersen, Risdiplam, and Onasemnogene abeparvovec have markedly improved survival and motor outcomes, they are not curative, and many patients continue to exhibit residual weakness, metabolic instability, and heterogeneous responses. This underscores the need for SMN-independent therapeutic strategies and robust biomarkers to enable personalised disease management. We investigated how SMN deficiency disrupts amino acid metabolism and neurotransmission across central and peripheral systems, integrating data from SMA mouse models, Drosophila, and patient biofluids. First, we show that excitatory amino acids, including L-glutamate, L-glutamine, D-serine, and D-aspartate, are dysregulated in the CNS and cerebrospinal fluid (CSF) of SMA, compromising glutamatergic neurotransmission—supplementation with D-serine improved motor performance in severe SMA mice, identifying a tractable metabolic target. Second, we discovered a selective deficiency of L-arginine in the spinal cord of SMA mice and in CSF from SMA1 patients, which Nusinersen restored in severe cases. Given L-arginine’s dual role in nitric oxide signalling and nitrogen/energy metabolism, this finding links SMN loss to both synaptic and vascular dysfunction. Third, we identified taurine deficiency in the SMA mice brainstem and CSF of patients, also corrected by Nusinersen in SMA1, nominating an additional candidate for adjunctive therapy. Extending beyond the CNS, systematic profiling in SmnΔ7 mice revealed widespread depletion of L-arginine and L-alanine across skeletal muscle, liver, kidney, and serum, alongside elevated glutamine/glutamate ratios, a systemic signature conserved in Drosophila SMA models. These metabolic changes were accompanied by stereospecific imbalances in D/L amino acids, as well as DNA damage and innate immune activation, establishing links between SMN loss, metabolic stress, and genome instability. Collectively, these studies establish amino acid dysregulation spanning central, peripheral, and stereospecific dimensions as a conserved hallmark of SMA. By integrating cross-species evidence, they highlight amino acids as grounded therapeutic candidates for SMN-independent intervention. This work provides a translational framework for developing biomarker-guided combination strategies to improve long-term outcomes in SMA."]},{"key":"dc:title","label":"Title","values":["SMN DEFICIENCY INDUCES NEUROACTIVE AMINOACIDS DYSMETABOLISM: BRIDGING INSIGHTS FROM PRECLINICAL MODELS TO CLINICAL EVIDENCE IN SMA PATIENTS"]}]}],"canonical_facts":{"dc:contributor":["supervisor: A. Usiello ; internal supervisor: F. Salvatore ; internal evaluator: E. M. Valente ; external evaluator: M. Bowerman","Bowerman","Melissa","A. Hassan"],"dc:creator":["HASSAN, AMBER"],"dc:date":["2025-12-19"],"dc:description":["ABSTRACT Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, driven by homozygous loss of the SMN1 gene and reduced SMN protein. Although disease-modifying therapies such as Nusinersen, Risdiplam, and Onasemnogene abeparvovec have markedly improved survival and motor outcomes, they are not curative, and many patients continue to exhibit residual weakness, metabolic instability, and heterogeneous responses. This underscores the need for SMN-independent therapeutic strategies and robust biomarkers to enable personalised disease management. We investigated how SMN deficiency disrupts amino acid metabolism and neurotransmission across central and peripheral systems, integrating data from SMA mouse models, Drosophila, and patient biofluids. First, we show that excitatory amino acids, including L-glutamate, L-glutamine, D-serine, and D-aspartate, are dysregulated in the CNS and cerebrospinal fluid (CSF) of SMA, compromising glutamatergic neurotransmission—supplementation with D-serine improved motor performance in severe SMA mice, identifying a tractable metabolic target. Second, we discovered a selective deficiency of L-arginine in the spinal cord of SMA mice and in CSF from SMA1 patients, which Nusinersen restored in severe cases. Given L-arginine’s dual role in nitric oxide signalling and nitrogen/energy metabolism, this finding links SMN loss to both synaptic and vascular dysfunction. Third, we identified taurine deficiency in the SMA mice brainstem and CSF of patients, also corrected by Nusinersen in SMA1, nominating an additional candidate for adjunctive therapy. Extending beyond the CNS, systematic profiling in SmnΔ7 mice revealed widespread depletion of L-arginine and L-alanine across skeletal muscle, liver, kidney, and serum, alongside elevated glutamine/glutamate ratios, a systemic signature conserved in Drosophila SMA models. These metabolic changes were accompanied by stereospecific imbalances in D/L amino acids, as well as DNA damage and innate immune activation, establishing links between SMN loss, metabolic stress, and genome instability. Collectively, these studies establish amino acid dysregulation spanning central, peripheral, and stereospecific dimensions as a conserved hallmark of SMA. By integrating cross-species evidence, they highlight amino acids as grounded therapeutic candidates for SMN-independent intervention. This work provides a translational framework for developing biomarker-guided combination strategies to improve long-term outcomes in SMA."],"dc:identifier":["http://dx.doi.org/10.13130/hassan-amber_phd2025-12-19","https://hdl.handle.net/2434/1201933","10.13130/hassan-amber_phd2025-12-19"],"dc:language":["eng"],"dc:publisher":["Università degli Studi di Milano"],"dc:relation":["numberofpages:408","alleditors:Bowerman, Melissa"],"dc:rights":["info:eu-repo/semantics/openAccess","license:Creative commons","license uri:http://creativecommons.org/licenses/by-sa/4.0/"],"dc:subject":["Spinal muscular atrophy (SMA)","Survival motor neuron (SMN)","Amino acid metabolism","L-arginine","L-alanine","Taurine","D-serine","Glutamine/glutamate ratio","D/L amino acid","Neuroinflammation","Cerebrospinal fluid (CSF)","Biomarker","Nusinersen","SmnΔ7 mouse model","Drosophila SMA model","Translational neuroscience","Settore BIOS-07/A - Biochimica","Settore BIOS-09/A - Biochimica clinica e biologia molecolare clinica","Settore MEDS-12/A - Neurologia","Settore MEDS-01/A - Genetica medica"],"dc:title":["SMN DEFICIENCY INDUCES NEUROACTIVE AMINOACIDS DYSMETABOLISM: BRIDGING INSIGHTS FROM PRECLINICAL MODELS TO CLINICAL EVIDENCE IN SMA PATIENTS"],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-27T20:18:48Z"}