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

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.

Keywords: Brain pathology; Parkinsonism; Proteome; Resilience.