Post‐translational protein modifications of transthyretin in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease, is progressive, fatal and poorly understood. Currently, established and objective molecular markers for diagnosis and monitoring of ALS are lacking. Our laboratory previously identified transthyretin (TTR) as a candidate protein biomarker for ALS using mass spectrometry‐based proteomics. We observed decreased TTR in cerebrospinal fluid (CSF) of ALS patients compared to controls. To further characterize the role of TTR, longitudinal CSF samples were analyzed. Using mass spectrometry, alterations in specific post‐translationally modified forms were observed. In particular, oxidative modifications of TTR at the sole cysteine residue [including adducts with cysteine or cysteinylglycine] were altered in ALS. These modified forms did not change over the course of the disease nor did they correlate with measures of disease progression. Enzyme‐linked immunosorbent assays (ELISA) specific for total TTR showed no significant change in TTR protein levels over the course of the disease suggesting that altered post‐translational protein modifications as opposed to total protein levels are important. As modifications of TTR at this residue are critical for stabilization of the tetrameric form of the protein, the functional importance of these alterations and their impact on protein aggregation are being further investigated.Research Support: NIH grant ES013469 (RB); NIH T32 EB001026 (CK); NIH T32 05 TL1 RR024155‐02 (CK)