A human proteogenomic-cellular framework identifies KIF5A as a modulator of astrocyte process integrity with relevance to ALS.
Genome-wide association studies identified several disease-causing mutations in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the contribution of genetic variants to pathway disturbances and their cell type-specific variations, especially in glia, is poorly understood. We integrated ALS GWAS-linked gene networks with human astrocyte-specific multi-omics datasets to elucidate pathognomonic signatures. It predicts that KIF5A, a motor protein kinesin-1 heavy-chain isoform, previously detected only in neurons, can also potentiate disease pathways in astrocytes. Using postmortem tissue and super-resolution structured illumination microscopy in cell-based perturbation platforms, we provide evidence that KIF5A is present in astrocyte processes and its deficiency disrupts structural integrity and mitochondrial transport. We show that this may underly cytoskeletal and trafficking changes in SOD1 ALS astrocytes characterised by low KIF5A levels, which can be rescued by c-Jun N-terminal Kinase-1 (JNK1), a kinesin transport regulator. Altogether, our pipeline reveals a mechanism controlling astrocyte process integrity, a pre-requisite for synapse maintenance and suggests a targetable loss-of-function in ALS.
Acknowledgements: The authors are grateful to the funders. This project and the A.L. laboratory were funded by the Medical Research Council (UKRI MRC UK, MR/P008658/1; MR/X006867/1 to A.L.). Funding to support K.SZ. was provided by MRC UK (to A.L.), the IBRO Return Home Fellowship 2022 and the NKFIH/OTKA FK 142223 grant. I.B-H. was funded by Open Targets. We thank Matthew Gratian for his assistance with super-resolution microscopy, Dr András Füredi for providing MitoBright Red as a gift, and Professors Evan Reid, Stephen Sawcer, and Aviva Tolkovsky for their comments on our manuscript.
Medical Research Council (MR/P008658/1)