Cerebrospinal fluid HOMER1 and NPTX2 as candidate signatures in early-stage multiple system atrophy-parkinsonism

Different morphological and pathological features of abnormal α-synuclein in synucleinopathies-multiple system atrophy (MSA) and Lewy body diseases, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB)-may underlie disease-specific synaptic dysfunction. To compare synaptic profiles associated with abnormal α-synuclein, we examined temporal lobe tissues from patients with MSA (N = 4), DLB (N = 5), and controls (N = 9). We further analysed cerebrospinal fluid (CSF) samples from patients with early-stage MSA-parkinsonism (MSA-P: N = 8) and PD (N = 8) to determine whether synaptic alterations observed in brain tissue are reflected in CSF. Immunoblotting revealed significantly reduced levels of homer protein homolog 1 (HOMER1) and neuronal pentraxin-2 (NPTX2) in DLB brains than in controls, whereas levels of protein phosphatase 3 catalytic subunit α and calcineurin subunit B type 1 were significantly increased. In contrast, brains from patients with MSA-P exhibited significant elevations in disks large homolog 2 and HOMER1 relative to those in controls. Consistent with these findings, CSF levels of HOMER1 and NPTX2 were significantly lower in PD than in MSA-P. Notably, CSF HOMER1 levels showed a significant positive correlation with neurofilament light chain, a marker of neurodegeneration. Exploratory receiver operating characteristic analyses may help distinguish early-stage MSA-P from PD. These findings indicate that disease-specific synaptic alterations associated with abnormal α-synuclein are reflected in CSF, heightening the potential utility of synaptic proteins as candidate CSF signatures in early-stage MSA-P.