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Ubiquitin-Proteasome System Dyeregulation in Alzheimer's Disease Impacts Protein Abundance.

ABSTRACT: Alzheimer’s disease is a relentlessly progressive, fatal neurodegenerative disorder associated with widespread aberrant proteomic changes. The full extent of protein dysfunctions in AD and their impact on cellular physiology remains unknown. Here, we used plexDIA, a proteomic profiling approach that parallelizes the acquisition of samples and peptides, to characterize proteomic changes in AD. Using human dorsolateral prefrontal cortex tissue, we identified 281 differentially abundant proteins between AD and non-AD, including multiple AD-associated proteins, as well as many proteins with no known role in AD. By systematically analyzing cellular compartment-specific shifts in protein abundance, we identified an AD specific decrease in levels of the 20S proteasome, the catalytic core of the cell’s primary protein degradation pathway. Many proteasome substrate proteins were negatively correlated with 20S levels and increased in AD, suggesting reduced 20S levels lead to abnormal protein accumulation. By analyzing proteins increased in AD, we identify key properties of such proteins. Namely, they have highly specific subcellular localizations and fast degradation rates, they contain signal sequences that allow them to be targeted for proteasomal degradation, and they are targeted by quality control pathways that recognize mislocalized proteins. Furthermore, we identify coherent sets of ubiquitin system enzymes, proteins that mark substrates for proteasomal degradation, whose levels robustly discriminate AD from non ADsamples. One subset exhibited consistent increases in AD, while consistent decreases were observed in the other, revealing complex alterations in substrate targeting pathways. Taken together, our results suggest that decreased ubiquitin proteasome system capacity and impaired clearance of short-lived and mislocalized proteins contribute substantially to proteopathic burden in AD

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Corinna Friedrich

LAB HEAD: Nikolai Slavov

PROVIDER: PXD064265 | Pride | 2025-05-27

REPOSITORIES: Pride

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			Action	DRS
	2024-04-25_combined_labled.raw	Raw
	2024-07-03_CF_C32_plex10.raw	Raw
	2024-07-03_CF_C32_plex11.raw	Raw
	2024-07-03_CF_C32_plex7.raw	Raw
	2024-07-03_CF_C32_plex8.raw	Raw

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Ubiquitin-Proteasome System Dyeregulation in Alzheimer's Disease Impacts Protein Abundance.

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