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 Huα-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
Huα-Syn­(A53T) 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).