TY - JOUR
T1 - Targeted plasma proteomics uncover proteins associated with KIF5A-linked SPG10 and ALS spectrum disorders
AU - Dulski, Jarosław
AU - Boddapati, Arun K.
AU - Risi, Barbara
AU - Iruzubieta, Pablo
AU - Orlacchio, Antonio
AU - Fernández-Torrón, Roberto
AU - Castillo-Triviño, Tamara
AU - López de Munain, Adolfo
AU - Vucic, Steve
AU - Padovani, Alessandro
AU - Kaat, Laura Donker
AU - Barakat, Tahsin Stefan
AU - Petrucelli, Leonard
AU - Prudencio, Mercedes
AU - Landers, John E.
AU - Weishaupt, Jochen H.
AU - Prokop, Andreas
AU - Filosto, Massimiliano
AU - Wszolek, Zbigniew K.
AU - Pant, Devesh C.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2026/1/15
Y1 - 2026/1/15
N2 - 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 multiplex NULISA targeted platform to analyze plasma proteome from KIF5A-linked SPG10 and ALS individuals and compare them 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 individuals. Moreover, these findings can now be used to gain mechanistic understanding of axonopathies linking to N- versus C-terminal KIF5A variants affecting both central and peripheral nervous systems.
AB - 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 multiplex NULISA targeted platform to analyze plasma proteome from KIF5A-linked SPG10 and ALS individuals and compare them 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 individuals. Moreover, these findings can now be used to gain mechanistic understanding of axonopathies linking to N- versus C-terminal KIF5A variants affecting both central and peripheral nervous systems.
KW - KIF5A, spastic paraplegia-10, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease type 2, proteomics, neurofilament light chain, axonopathy
UR - https://www.scopus.com/pages/publications/105015511105
UR - https://www.scopus.com/pages/publications/105015511105#tab=citedBy
U2 - 10.1016/j.xhgg.2025.100498
DO - 10.1016/j.xhgg.2025.100498
M3 - Article
C2 - 40873038
AN - SCOPUS:105015511105
SN - 2666-2477
VL - 7
JO - Human Genetics and Genomics Advances
JF - Human Genetics and Genomics Advances
IS - 1
M1 - 100498
ER -