Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS

Springer Science and Business Media LLC - Tập 146 - Trang 451-475 - 2023
Amr Aly1, Zsofia I. Laszlo2, Sandeep Rajkumar1, Tugba Demir1, Nicole Hindley2, Douglas J. Lamont3, Johannes Lehmann1, Mira Seidel1, Daniel Sommer1, Mirita Franz-Wachtel4, Francesca Barletta5, Simon Heumos5,6, Stefan Czemmel5, Edor Kabashi7, Albert Ludolph8,9, Tobias M. Boeckers1,9, Christopher M. Henstridge2, Alberto Catanese1,9
1Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany
2Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK
3FingerPrints Proteomics Facility, Discovery Centre, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
4Proteome Center Tübingen, University of Tübingen, Tübingen, Germany
5Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany
6Biomedical Data Science, Department of Computer Science, University of Tübingen, Tübingen, Germany
7Laboratory of Translational Research for Neurological Disorders, Imagine Institute, Université de Paris, INSERM, Paris, France
8Department of Neurology, Ulm University School of Medicine, Ulm, Germany
9German Center for Neurodegenerative Diseases (DZNE), Ulm Site, Germany

Tóm tắt

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.

Tài liệu tham khảo

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