Proteome-Wide Discovery of Cortical Proteins That May Provide Motor Resilience to Offset the Negative Effects of Pathologies in Older Adults

Abstract

Abstract Background Motor resilience proteins have not been identified. This proteome-wide discovery study sought to identify proteins that may provide motor resilience. Methods We studied the brains of older decedents with annual motor testing, postmortem brain pathologies, and proteome-wide data. Parkinsonism was assessed using 26 items of a modified United Parkinson Disease Rating Scale. We used linear mixed-effect models to isolate motor resilience, defined as the person-specific estimate of progressive parkinsonism after controlling for age, sex, and 10 brain pathologies. A total of 8 356 high-abundance proteins were quantified from dorsal lateral prefrontal cortex using tandem mass tag and liquid chromatography–mass spectrometry. Results There were 391 older adults (70% female), mean age 80 years at baseline and 89 years at death. Five proteins were associated with motor resilience: A higher level of AP1B1 (Estimate −0.504, SE 0.121, p = 3.12 × 10−5) and GNG3 (Estimate −0.276, SE 0.068, p = 4.82 × 10−5) was associated with slower progressive parkinsonism. By contrast, a higher level of TTC38 (Estimate 0.140, SE 0.029, p = 1.87 × 10−6), CARKD (Estimate 0.413, SE 0.100, p = 3.50 × 10−5), and ABHD14B (Estimate 0.175, SE 0.044, p = 6.48 × 10−5) was associated with faster progressive parkinsonism. Together, these 5 proteins accounted for almost 25% of the variance of progressive parkinsonism above the 17% accounted for by 10 indices of brain pathologies. Discussion Cortical proteins may provide more or less motor resilience in older adults. These proteins are high-value therapeutic targets for drug discovery that may lead to interventions that maintain motor function despite the accumulation of as yet untreatable brain pathologies.