Objective: To characterize the cerebrospinal fluid (CSF) profile, as well as to identify potential biomarkers, we quantitatively compared the CSF proteome of FXTAS patients with age-matched controls using mass spectrometry.

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS), first described in 2001, is a progressive neurodegenerative disorder caused by a ‘premutation’ size expansion of 55-200 CGG repeats in the fragile X mental retardation 1 (FMR1) gene. To date, the biological mechanism causing this condition is still not well understood, as not all premutation carriers develop FXTAS.  Biomarker development is critical in the disease as clinical trials have commenced in the disorder.

Method: FXTAS patients (n=10) were recruited from the Rush FXTAS Clinic and lumbar punctures were performed. Control CSF (n=6)  was obtained from BioChemed Services. HSA depletion was performed using a multiple affinity removal column. After protein determination, proteolytic cleavage, iTRAO labeling, offline high pH reverse-phase fractionation, and nanoLC-MS/MS detection were completed.  Protein identification was obtained via Proteome Discoverer and analyzed in Scaffold.

Results: 415 proteins were identified and 97 were observed to be altered in FXTAS participants. The proteins identified suggest changes in acute phase response signaling, LXR/RXR activation, and FXR/RXR activation, which are the main pathways affected in FXTAS. Additionally, we detected changes in many proteins (amyloid-like protein 2, contactin-1, afamin, cell adhesion molecule 4, NPC intracellular cholesterol transporter 2, and capthesin B) that had been previously noted to hold important roles in other movement disorders. Specific to RXR pathways, several apolipoproteins (APOA1, APOA2, APOA4, APOC2, and APOD) showed significant changes in the CSF of FXTAS patients.

Conclusion: The proteins differentially detected in the CSF of FXTAS participants have also been associated with other neurodegenerative disorders.  Additionally, alterations of expression in apolipoproteins suggest that lipid changes along the disease course should be a future area of focus. These results warrant larger sample sizes to determine the utility of CSF parameters for biomarker development.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterization-of-the-cerebrospinal-fluid-proteome-in-patients-with-fragile-x-associated-tremor-ataxia-syndrome/