Sensing α‐Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration

Abstract

Parkinson's disease and other synucleinopathies are characterized by the accumulation of aggregated α‐synuclein in intracellular proteinaceous inclusions. The progressive nature of synucleinopathies seems to be related to the cell‐to‐cell spreading of α‐synuclein pathology, and several possible mechanisms have been put forward to explain this phenomenon. In our recent study, we found that α‐synuclein oligomers interact with cellular prion protein in glutamatergic synapses. This interaction triggered a signaling cascade involving phosphorylation of Fyn kinase and activation of the N‐methyl‐d‐aspartate receptor, thereby leading to synaptic dysfunction. Here, we present relevant plasma membrane proteins that have been described to interact with α‐synuclein and discuss the possible pathological implications. We focus primarily on the prion protein and propose a pathological mechanism in which the interaction between α‐synuclein and prion protein leads to the formation of cofilin/actin rods, culminating in long‐term potentiation impairment and cognitive dysfunction. We posit that deciphering the mechanisms involved in sensing specific forms of extracellular α‐synuclein and transducing this information may prove invaluable in our quest to devise novel diagnostic and therapeutic approaches in PD and other synucleinopathies. © 2018 International Parkinson and Movement Disorder Society

Prion-Like Mechanisms in Parkinson’s Disease

“…This cooperation fosters the transmission of α-syn between cells and causes synaptic dysfunction via a signaling cascade acting through phosphorylation of Fyn kinase and activation of the N-methyl-D-aspartate receptor (NMDAR). α-syn-PrP C binding induces cofilin/actin rods formation, which changes actin dynamics, resulting in rearrangements of cytoskeleton and eventual synaptic dysfunction (Clavaguera et al, 2015; Bras et al, 2018; Surguchev et al, 2019). Equally, α-syn amyloids blocked the replication of PrP Sc in vitro and ex vivo (Aulic et al, 2017).…”

Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy

“…In this study, we aimed at characterizing mechanisms downstream of αSyn hippocampal pathology underlying synaptic impairment and cognitive dysfunction in Lewy Body dementias. We focused on the actin cytoskeleton, not only due to its critical role in synaptic function, but also because a link between this cell component and αSyn has been increasingly supported by the literature 9, 10 . One of the consequences of the dysregulation of actin dynamics in neurodegenerative disorders is the formation of cofilin-actin rods.…”

Cell Responses to Extracellular α-Synuclein

“…A number of recent studies suggests that extracellular α-synuclein acts as a specific ligand for cell surface receptors [11,12,13,14]. Oligomeric α-synuclein binding to cell surface receptors induces the transmission of signal into cells and causes a variety of biochemical and physiological reactions, including Ca 2+ dysregulation [15], synaptic dysfunction, neurodegeneration, cognitive deficit, etc.…”

“…This cooperation facilitates the transfer of α-synuclein between cells [11]. Furthermore, such interaction causes synaptic dysfunction via a signaling cascade acting through phosphorylation of Fyn kinase and activation of the N-methyl-D-aspartate receptor [11,12,13,14]. Apparently, α-synuclein and PrPC do not form a tight complex, but are involved in short-term transitory interaction that alters α-synuclein conformation and properties.…”

“…As shown above, synucleins modulate many intracellular processes and interact with a plethora of proteins, affecting signaling pathways [11,12,13,14,16,23,26,29,32]. What structural elements of these proteins ensure their binding diversity and involvement in many cellular functions?…”