Journal Article

DZNE-2023-00740

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS

Aly, A. ; Laszlo, Z. I. ; Rajkumar, S. ; Demir, T. ; Hindley, N. ; Lamont, D. J. ; Lehmann, J. ; Seidel, M. ; Sommer, D. ; Franz-Wachtel, M. ; Barletta, F. ; Heumos, S. ; Czemmel, S. ; Kabashi, E. ; Ludolph, A.DZNE* ; Böckers, T.DZNE* ; Henstridge, C. M. ; Catanese, A.DZNE*

2023
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-023-02611-y

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting upper and lower motoneurons. Several functionally heterogeneous genes have been associated with the familial form of this disorder (fALS), depicting an extremely complex pathogenic landscape. This heterogeneity has limited the identification of an effective therapy, and this bleak prognosis will only improve with a greater understanding of convergent disease mechanisms. Recent evidence from human post-mortem material and diverse model systems has highlighted the synapse as a crucial structure actively involved in disease progression, suggesting that synaptic aberrations might represent a shared pathological feature across the ALS spectrum. To test this hypothesis, we performed the first comprehensive analysis of the synaptic proteome from post-mortem spinal cord and human iPSC-derived motoneurons carrying mutations in the major ALS genes. This integrated approach highlighted perturbations in the molecular machinery controlling vesicle release as a shared pathomechanism in ALS. Mechanistically, phosphoproteomic analysis linked the presynaptic vesicular phenotype to an accumulation of cytotoxic protein aggregates and to the pro-apoptotic activation of the transcription factor c-Jun, providing detailed insights into the shared pathobiochemistry in ALS. Notably, sub-chronic treatment of our iPSC-derived motoneurons with the fatty acid docosahexaenoic acid exerted a neuroprotective effect by efficiently rescuing the alterations revealed by our multidisciplinary approach. Together, this study provides strong evidence for the central and convergent role played by the synaptic microenvironment within the ALS spinal cord and highlights a potential therapeutic target that counteracts degeneration in a heterogeneous cohort of human motoneuron cultures.

Keyword(s): Humans (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Neurodegenerative Diseases: pathology (MeSH) ; Proteomics (MeSH) ; Superoxide Dismutase-1: genetics (MeSH) ; Motor Neurons: metabolism (MeSH) ; ALS ; Motoneuron ; Proteomics ; Spinal cord ; Synapse ; hiPSC ; Superoxide Dismutase-1

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Contributing Institute(s):

1. Translational Protein Biochemistry (AG Böckers)
2. Clinical Study Center Ulm (Clinical Study Center Ulm)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article (Erratum/Correction) Aly, A. ; Laszlo, Z. I. ; Rajkumar, S. ; Demir, T. ; Hindley, N. ; Lamont, D. J. ; Lehmann, J. ; Seidel, M. ; Sommer, D. ; Franz-Wachtel, M. ; Barletta, F. ; Heumos, S. ; Czemmel, S. ; Kabashi, E. ; Ludolph, A.DZNE* ; Boeckers, T. M.DZNE* ; Henstridge, C. M. ; Catanese, A. (Last author)DZNE*
Correction to: Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS.
Acta neuropathologica 146(5), 783 - 783 (2023) [10.1007/s00401-023-02630-9]2023   Files  Fulltext by Pubmed Central BibTeX | EndNote: XML, Text | RIS

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