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Open Access 01-06-2024 | Spinal Muscular Atrophy | Original Paper

Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy

Authors: Andreas Roos, Linda-Isabell Schmitt, Christina Hansmann, Stefanie Hezel, Schahin Salmanian, Andreas Hentschel, Nancy Meyer, Adela Della Marina, Heike Kölbel, Christoph Kleinschnitz, Ulrike Schara-Schmidt, Markus Leo, Tim Hagenacker

Published in: Acta Neuropathologica | Issue 1/2024

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by recessive pathogenic variants affecting the survival of motor neuron (SMN1) gene (localized on 5q). In consequence, cells lack expression of the corresponding protein. This pathophysiological condition is clinically associated with motor neuron (MN) degeneration leading to severe muscular atrophy. Additionally, vulnerability of other cellular populations and tissues including skeletal muscle has been demonstrated. Although the therapeutic options for SMA have considerably changed, treatment responses may differ thus underlining the persistent need for validated biomarkers. To address this need and to identify novel marker proteins for SMA, we performed unbiased proteomic profiling on cerebrospinal fluid derived (CSF) from genetically proven SMA type 1–3 cases and afterwards performed ELISA studies on CSF and serum samples to validate the potential of a novel biomarker candidates in both body fluids. To further decipher the pathophysiological impact of this biomarker, immunofluorescence studies were carried out on spinal cord and skeletal muscle derived from a 5q-SMA mouse model. Proteomics revealed increase of LARGE1 in CSF derived from adult patients showing a clinical response upon treatment with nusinersen. Moreover, LARGE1 levels were validated in CSF samples of further SMA patients (type 1–3) by ELISA. These studies also unveiled a distinguishment between groups in improvement of motor skills: adult patients do present with lowered level per se at baseline visit while no elevation upon treatment in the pediatric cohort can be observed. ELISA-based studies of serum samples showed no changes in the pediatric cohort but unraveled elevated level in adult patients responding to future intervention with nusinersen, while non-responders did not show a significant increase. Additional immunofluorescence studies of LARGE1 in MN and skeletal muscle of a SMA type 3 mouse model revealed an increase of LARGE1 during disease progression. Our combined data unraveled LARGE1 as a protein dysregulated in serum and CSF of SMA-patients (and in MN and skeletal muscle of SMA mice) holding the potential to serve as a disease marker for SMA and enabling to differentiate between patients responding and non-responding to therapy with nusinersen.

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Title: Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy
Authors: Andreas Roos
Linda-Isabell Schmitt
Christina Hansmann
Stefanie Hezel
Schahin Salmanian
Andreas Hentschel
Nancy Meyer
Adela Della Marina
Heike Kölbel
Christoph Kleinschnitz
Ulrike Schara-Schmidt
Markus Leo
Tim Hagenacker
Publication date: 01-06-2024
Publisher: Springer Berlin Heidelberg
Keyword: Spinal Muscular Atrophy
Published in: Acta Neuropathologica / Issue 1/2024
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-024-02709-x

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Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy

Abstract

Keynote webinar | Spotlight on medication adherence

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