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Does Data-Independent Acquisition Data Contain Hidden Gems? A Case Study Related to Alzheimer's Disease

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One of the hallmarks of Alzheimer's disease (AD) is the neurofibrillary tangle (NFT), of which the long-lived protein tau is a primary component. Although tau and its relationship to AD has been studied extensively, isomerization in tau has received relatively little attention, and the connection between tau isomerization and AD remains unexplored. 

In this publication we examine a large data set of human brain samples, revealing a striking relationship between AD status and aspartic acid isomerization in a peptide from tau. A surprising increase in isomer abundance was found in both autosomal dominant and sporadic AD samples relative to control brain samples not exhibiting AD. Quantitative analysis of proteins related to isomerization repair and autophagy revealed differences consistent with reduced autophagy in AD samples, including p62, a recognized indicator of autophagic inhibition. Our results suggest, but don't conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains.

Proteinaceous aggregation is a well-known observable in Alzheimer’s disease (AD), but failure and storage of lysosomal bodies within neurons is equally ubiquitous and actually precedes bulk accumulation of extracellular amyloid plaque. In fact, AD shares many similarities with certain lysosomal storage disorders though establishing a biochemical connection has proven difficult. 

In this publication we demonstrate that isomerization and epimerization, which are spontaneous chemical modifications that occur in long-lived proteins, prevent digestion by the proteases in the lysosome. These modified substrates are capable of inducing gradual lysosomal failure, which may play an important role in the cascade of events leading to the disrupted proteostasis, amyloid formation, and tauopathies associated with AD.

Spontaneous Isomerization of Long-Lived Proteins Provides a Molecular Mechanism for the Lysosomal Failure Observed in Alzheimer's Disease

About Us

The Julian laboratory is housed within Chemical Sciences at the University of California, Riverside. We have diverse research interests including: protein structure/folding, post translational modifications, radical chemistry, and aging.

The development of novel technologies continues to be a significant driver of science. For example, the invention of electrospray ionization enabled analysis of peptides and proteins by mass spectrometry, spurring tremendous advances and growth in the field of proteomics and many others. The Julian group develops mass spectrometry based tools to analyze molecular chemistry and structure, with targets ranging from protein quaternary structure to subtle differences in peptide epimers or even small molecule lipid isomers. Although there are many excellent methods for examining structure, mass spectrometry is usually faster, more sensitive, and amenable to high-throughput experiments, enabling analysis of complicated biological samples.