Synaptic and cytoskeletal CSF signatures of motor neuron disease: the role of cyclase-associated protein 2

Cyclase-associated protein 2 (CAP2) is a synaptic actin-binding protein involved in cofilin-mediated spine remodelling, Alzheimer’s Disease synaptic failure and myofibril maintenance, indicating its potential involvement in motor neuron disease (MND). This study examined cerebrospinal fluid (CSF) levels of CAP2 in 60 patients with MND and 40 healthy controls (HC) to assess its diagnostic and prognostic value and its relationship with neuronal, glial and synaptic markers. Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated and total tau (p-Tau 181, t-Tau), CAP2 and synaptosomal-associated protein 25 (SNAP-25) were quantified using ELISA, Lumipulse and SIMOA platforms. MND patients displayed increased GFAP, NfL, t-Tau, p-Tau 181 levels and CAP2 while SNAP-25 was reduced. CAP2 correlated with tau markers, but not with NfL or GFAP. Unlike NfL, which was higher in upper motor neuron–predominant cases and predicted faster progression and poorer survival, CAP2 did not vary with disease subtypes or severity. The study showed that CAP2 is associated with MND independently from neuronal, glial and presynaptic dysfunction. Integrating CAP2 into multi-marker panels could enhance understanding of synaptic pathology in MND.