Rustogi, N. | bioRxiv Science

bioRxiv2018

Regional protein expression in human Alzheimer’s brain correlates with disease severity

Alzheimers disease (AD) is a progressive neurodegenerative disorder that currently affects 36 million people worldwide with no effective treatment available. Development of AD follows a distinctive pattern in the brain and is poorly modelled in animals. Therefore, it is vital to widen both the spatial scope of the study of AD and prioritise the study of human brains. Here we show that functionally distinct human brain regions show varying and region-specific changes in protein expression. These changes provide novel insights into the progression of disease, novel AD-related pathways, the presence of a gradient of protein expression change from less to more affected regions, and the presence of a protective protein expression profile in the cerebellum. This spatial proteomics analysis provides a framework which can underpin current research and opens new avenues of interest to enhance our understanding of molecular pathophysiology of AD, provides new targets for intervention and broadens the conceptual frameworks for future AD research.

neuroscience↗

bioRxiv2017

Insights into the molecular changes associated with postnatal human brain development: an integrated transcriptomics and proteomics study

Healthy cortical development depends on precise regulation of transcription and translation. However, the dynamics of how proteins are expressed, function and interact across postnatal human cortical development remain poorly understood. We surveyed the proteomic landscape of 69 dorsolateral prefrontal cortex samples across seven stages of postnatal life and integrated these data with paired transcriptome data. We detected 911 proteins by liquid chromatography-mass spectrometry, and 83 were significantly associated with postnatal age (FDR p < 0.05). Network analysis identified three modules of co-regulated proteins correlated with age, including two modules with increasing expression involved in gliogenesis and NADH-metabolism and one neurogenesis-related module with decreasing expression throughout development. Integration with paired transcriptome data revealed that these age-related protein modules overlapped with RNA modules and displayed collinear developmental trajectories. Importantly, RNA expression profiles that are dynamically regulated throughout cortical development display tighter correlations with their respective translated protein expression compared to those RNA profiles that are not. Moreover, the correspondence between RNA and protein expression significantly decreases as a function of cortical aging, especially for genes involved in myelination and cytoskeleton organization. Finally, we used this data resource to elucidate the functional impact of genetic risk loci for intellectual disability, converging on gliogenesis, myelination and ATP-metabolism modules in the proteome and transcriptome. We share all data in an interactive, searchable companion website. Collectively, our findings reveal dynamic aspects of protein regulation and provide new insights into brain development, maturation and disease.

neuroscience↗