The Cellular Prion Protein—ROCK Connection: Contribution to Neuronal Homeostasis and Neurodegenerative Diseases

Abstract

Amyloid-based neurodegenerative diseases such as prion, Alzheimer's, and Parkinson's diseases have distinct etiologies and clinical manifestations, but they share common pathological events. These diseases are caused by abnormally folded proteins (pathogenic prions PrPSc in prion diseases, β-amyloids/Aβ and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease) that display β-sheet-enriched structures, propagate and accumulate in the nervous central system, and trigger neuronal death. In prion diseases, PrPSc-induced corruption of the physiological functions exerted by normal cellular prion proteins (PrPC) present at the cell surface of neurons is at the root of neuronal death. For a decade, PrPC emerges as a common cell surface receptor for other amyloids such as Aβ and α-synuclein, which relays, at least in part, their toxicity. In lipid-rafts of the plasma membrane, PrPC exerts a signaling function and controls a set of effectors involved in neuronal homeostasis, among which are the RhoA-associated coiled-coil containing kinases (ROCKs). Here we review (i) how PrPC controls ROCKs, (ii) how PrPC-ROCK coupling contributes to neuronal homeostasis, and (iii) how the deregulation of the PrPC-ROCK connection in amyloid-based neurodegenerative diseases triggers a loss of neuronal polarity, affects neurotransmitter-associated functions, contributes to the endoplasmic reticulum stress cascade, renders diseased neurons highly sensitive to neuroinflammation, and amplifies the production of neurotoxic amyloids.

The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis

“…A potential sign of disrupted proteostasis is abnormal protein oligomerization, which also increases the protein half-life by reducing the exposure of intrinsically disordered regions on proteins targeted for proteasomal recognition . This phenomenon has been observed for the aforementioned amyloid-β and α-synuclein proteins in the context of neurodegenerative diseases. − To evaluate the presence of oligomeric PACS-2 complexes, we treated 293T cells expressing PACS-2 WT or E209K with 1,4-bismaleimidobutane (BMB), a homobifunctional sulfhydryl cross-linker. The BMB treatment rendered higher molecular weight (>200 kDa) oligomers for both PACS-2 WT and E209K, while only monomeric (∼125 kDa) PACS-2 was observed in the DMSO-treated negative controls (Figures C and D).…”

Removal of Environmental Nanoparticles Increases Protein Synthesis and Energy Production in Healthy Humans

“…Protein synthesis, which is mainly performed by the endoplasmic reticulum, is a delicate process that is easily uncoupled and hampered. From viral or bacterial infections ( Chamberlain and Anathy, 2020 ; Alshareef et al, 2021 ) to the development of any neurodegenerative disease ( Ghemrawi and Khair, 2020 ; Schneider et al, 2021 ), reticulum stress is a common cellular manifestation of such pathologies. Endoplasmic reticulum stress regulates mTOR, which in turn, modulates cell growth and protein synthesis through the phosphorylation of p70S6K.…”

Neuron Scale Modeling of Prion Production with the Unfolded Protein Response

“…Other studies, investigating the role of UPR upon neurodegeneration in prion diseases, indicate that a high concentration of PrP Sc triggers ER stress. This activates the UPR and results in a transient global shutdown of protein synthesis [27,26,43,38,33]. The latter studies, which will constitute the basis of our biological assumptions, lead us to suggest that UPR indirectly downregulates PrP Sc : by preventing global protein translation, UPR activation shuts down the production of PrP c which ultimately hampers the production of PrP Sc .…”

“…[18,39,20,21]). Nonetheless, studies seem to agree on the fact that accumulation 2 of abnormally folded proteins triggers ER stress that subsequently activate the UPR [27,39,20,38,33].…”

“…In the context of prion-diseases, knowledge becomes clearer as some studies performed on mice highlight links between PrP Sc aggregates, ER stress and UPR mechanism [19,45,27,26,43,38,33]. For instance, some works seem to indicate that UPR downregulates PrP Sc through secreted chaperones acting over the extracellular proteostasis [15,16].…”