Abstract
Alzheimer’s Disease is driven by protein aggregation and is characterized by accumulation of Tau protein into neurofibrillary tangles. In healthy neurons the cellular protein quality control is successfully in charge of protein folding, which raises the question to which extent this control is disturbed in disease. Here, we describe that brain cells in Alzheimer’s Disease show very specific derailment of the protein quality control network. We performed a meta-analysis on the Alzheimer’s Disease Proteome database, which provides a quantitative assessment of disease-related proteome changes in six brain regions in comparison to age-matched controls. We noted that levels of all paralogs of the conserved Hsp90 chaperone family are reduced, while most other chaperones – or their regulatory co-chaperones - do not change in disease. The notable exception is a select group consisting of the stress inducible HSP70, its nucleotide exchange factor BAG3 – which links the Hsp70 system to autophagy - and neuronal small heat shock proteins, which are upregulated in disease. They are all members of a cascade controlled in the stress response, channeling proteins towards a pathway of chaperone assisted selective autophagy. Together, our analysis reveals that in an Alzheimer’s brain, with exception of Hsp90, the players of the protein quality control are still present in full strength, even in brain regions most severely affected in disease. The specific upregulation of small heat shock proteins and HSP70:BAG3, ubiquitous in all brain areas analyzed, may represent a last, unsuccessful attempt to advert cell death.
Highlights
Neurodegenerative diseases are a group of diseases characterized by progressive neuronal degeneration, of which Alzheimer’s Disease (AD) is the most prominent one
To test the hypothesis that the protein quality control (PQC) capacity decreases in AD, we performed a meta-analysis of the proteomics data provided by the Unwin laboratory, which is freely available at http://www.dementia-proteomes-project.manchester.ac.uk/ Proteome/Search (Xu et al, 2019; Figure 1A)
We assessed the significance of increase or decrease in protein levels for each PQC component considering the following: (i) a change relevant to the disease is likely to show a pattern reflecting the extent of how severely brain regions are affected by AD. (ii) The extent of the alteration in protein levels, as chaperones act stoichiometrically. (iii) The false-discovery rate (FDR), indicating an estimate on variability of the data
Summary
Neurodegenerative diseases are a group of diseases characterized by progressive neuronal degeneration, of which Alzheimer’s Disease (AD) is the most prominent one. Symptoms of AD include severe memory loss and cognitive decline and are often accompanied by changes in personality (Bature et al, 2017). AD shows the accumulation of two distinct proteins; extracellular plaques of amyloid-β and intracellular formation of neurofibrillary tangles of Tau; a microtubule associated protein assisting in microtubule stability and regulating axonal transport (Drubin and Kirschner, 1986; Goedert et al, 2017). Tau dissociates from the microtubules and aggregates into Tau fibrils, a process leading to cellular death. The exact underlying molecular mechanism of Tau aggregation is still unknown.
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