Analysis of Brain Protein Stability Changes in Mouse Models of Normal Aging and α-Synucleinopathy Reveals Age- and Disease-Related Differences

Here, we utilize the stability of proteins from rates of oxidation (SPROX) technique, to profile the thermodynamic stabilities of proteins in brain tissue cell lysates from Hu alpha-Syn(A53T) transgenic mice at three time points including at 1 month (n = 9), at 6 months (n = 7), and at the time (between 9 and 16 months) a mouse became symptomatic (n = 8). The thermodynamic stability profiles generated here on 332 proteins were compared to thermodynamic stability profiles generated on the same proteins from similarly aged wild-type mice using a two-way unbalanced analysis of variance (ANOVA) analysis. This analysis identified a group of 22 proteins with age-related protein stability changes and a group of 11 proteins that were differentially stabilized in the Hu alpha-Syn(AS3T) transgenic mouse model. A total of 9 of the 11 proteins identified here with disease-related stability changes have been previously detected in human cerebral spinal fluid and thus have potential utility as biomarkers of Parkinson's disease (PD). The differential stability observed for one protein, glutamate decarboxylase 2 (Gad2), with an age-related change in stability, was consistent with the differential presence of a known, age-related truncation product of this protein, which is shown here to have a higher folding stability than full-length Gad2. Mass spectrometry data were deposited at ProteomeXchange (PXD016985).

Automated summary

Using the SPROX technique, the study analyzed the thermodynamic stabilities of proteins in brain tissue cell lysates from Hu α-Syn(A53T) transgenic mice at different time points. It identified a group of proteins with age-related stability changes and a group with differential stability in the transgenic mouse model. Some of these proteins have been previously detected in human cerebral spinal fluid and could potentially serve as biomarkers for Parkinson's disease.