TECPR2a positive regulator of autophagy is implicated in healthy brain ageing

ABSTRACT Understanding the healthy brain aging process is key to uncovering the mechanisms leading to pathological age-related neurodegeneration, including progression to Alzheimer’s disease (AD). Here, we report the first deep whole genome sequencing study aiming to identify variants that are associated specifically to healthy brain aging defined on both clinical and neuropathological level, thus tacking the issue of pathological heterogeneity that often underlies a clinical AD diagnosis. We studied samples from the VITA brain bank and followed an extreme phenotypic ends study design comparing neuropathologically “healthy” aging individuals above 80 years of age with pure AD patients of the same age. Focusing on the extreme ends of the phenotypic distribution, and potentially functional variants, we discover a single variant (rs10149146) carried by 53.6% of the “healthy” brain elderly individuals in our study (15/28 individuals) and none of the 12 AD cases. This variant lies on the autophagy and cell cycle associated TECPR2 gene. Autophagy dysfunction has been previously implicated in multiple progressive neurodegenerative diseases. An additional non-synonymous variant on the CINP gene (encoding a cell-cycle checkpoint protein) is also found in 46% of healthy controls and absent from all the AD cases. TECPR2 and CINP appear to be “partner” genes in terms of regulation and their associated transcription factors have been previously implicated in AD and neurodegeneration. Our study is the first to support the hypothesis that a TECPR2 non-synonymous variant carries a significant neuroprotective effect pointing to key molecules for the involvement of autophagy and cell cycle control in protection from neurodegeneration.