ABERRANT POLYUBIQUITOME PROFILE IN DOWN SYNDROME AND ALZHEIMER DISEASE BRAIN

Abstract

Among the putative mechanisms proposed to be common factors in Down Syndrome (DS) and Alzheimer disease (AD) neuropathology, deficits in protein quality control has emerged as a unifying mechanism of neurodegeneration. DS offers a unique model to investigate the early molecular changes that disturb neuronal homeostasis and that with age lead slowly, but irreversibly, to neuronal death [1]. Considering that disturbance of protein degradative systems are present in DS and AD and that oxidized/misfolded proteins require poly-ubiquitination for degradation via the ubiquitin proteasome system, this study investigated if the dysregulation of protein poly-ubiquitination is associated with AD neurodegeneration in DS. Post-mortem brains from DS, before and after development of AD, and AD cases and their age-matched controls were analyzed. Polyubiquitinated proteins were isolated by affinity chromatography and analyzed by proteomics approach. Proteins showing altered pattern of polyubiquitination among the different groups were identified by mass spectrometry. In addition, the extent of poly-K48 and poly-K63 modifications were also analyzed. This is the first study showing alteration of the polyubiquitination profile in DS, prior and after development of AD, and AD brain compared with healthy controls. The accumulation of polyubiquitinated proteins, either K48 or K63 localized, is present in younger cases with DS without significant AD pathology, suggesting an early aging phenotype. We also found that oxidation is coupled with polyubiquitination for several identified proteins, which are mainly involved in protein quality control and energy metabolism. In the presence of reduced proteasomal activity and impaired autophagy, oxidized/misfolded proteins tagged by polyubiquitin chains may accumulate and contribute to a toxic environment for neurons in DS and AD. Considering that the development of AD pathology is age dependent in DS and shows characteristic features of AD, identification of common polyubiquitinated proteins in both DS and AD can provide novel insights on the overlapping mechanisms that may lead from normal aging to the development of AD. [1] Wiseman FK et al. Nat Rev Neurosci 2015, 16(9): 564–74. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome.