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bioRxiv · 10.1101/2025.04.29.651203

Targeted plasma proteomics uncover novel proteins associated with KIF5A-linked SPG10 and ALS spectrum disorders

Dulski, J.·Boddapati, A.·Risi, B.·Iruzubieta, P.·Orlacchio, A.·Fernandez Torron, R.·Castillo Trivino, T.·Lopez De M Arregui, A.·Vucic, S.·Kaat, L. D.·Barakat, T. S.·Petrucelli, L.·Prudencio, M.·Landers, J. E.·Prokop, A.·Weishaupt, J. H.·Filosto, M.·Wszolek, Z. K.·Pant, D. C.
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Abstract

KIF5A (Kinesin family member 5A) is a motor protein that functions as a key component of the axonal transport machinery. Variants in KIF5A are linked to several neurodegenerative diseases, mainly spastic paraplegia type 10 (SPG10), Charcot-Marie-Tooth disease type 2 (CMT2), and amyotrophic lateral sclerosis (ALS). These diseases share motor neuron involvement but vary significantly in clinical presentation, severity, and progression. KIF5A variants are mainly categorized into N-terminal variants associated with SPG10/CMT2 and C-terminal variants linked to ALS. This study utilized a novel multiplex NULISA targeted platform to analyze plasma proteome from KIF5A-linked SPG10, ALS patients and compared to healthy controls. Our results revealed distinct proteomic signatures, with significant alterations in proteins related to synaptic function, and inflammation. Notably, neurofilament light polypeptide, a biomarker for neurodegenerative diseases, was elevated in KIF5A ALS but not in SPG10 patients. Moreover, these findings can now be taken forward to gain mechanistic understanding of axonopathies linking to N-vs C-terminal KIF5A variants affecting both central and peripheral nervous systems.

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Dulski, J., Boddapati, A., Risi, B., Iruzubieta, P., Orlacchio, A., Fernandez Torron, R., Castillo Trivino, T., Lopez De M Arregui, A., Vucic, S., Kaat, L. D., Barakat, T. S., Petrucelli, L., Prudencio, M., Landers, J. E., Prokop, A., Weishaupt, J. H., Filosto, M., Wszolek, Z. K., Pant, D. C.. 2025-05-02. Targeted plasma proteomics uncover novel proteins associated with KIF5A-linked SPG10 and ALS spectrum disorders. https://doi.org/10.1101/2025.04.29.651203

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