Extracellular alpha‐synuclein induces calpain‐dependent overactivation of cyclin‐dependent kinase 5 in vitro

Abstract

Edited by Jesus Avila Keywords:Parkinson's disease Alpha-synuclein Cyclin-dependent kinase 5 Phosphorylation p35 Calpain a b s t r a c t Extracellular alpha-synuclein (ASN) could be involved in the pathomechanism of Parkinson's disease (PD) via disturbances of calcium homeostasis, activation of nitric oxide synthase and oxidative/nitrosative stress. In this study we analyzed the role of cyclin-dependent kinase 5 (Cdk5) in the molecular mechanism(s) of ASN toxicity.We found that exposure of PC12 cells to ASN increases Cdk5 activity via calpain-dependent p25 formation and by enhancement of Cdk5 phosphorylation at Tyr15. Cdk5 and calpain inhibitors prevented ASN-evoked cell death. Our findings, indicating the participation of Cdk5 in ASN toxicity, provide new insight into how extracellular ASN may trigger dopaminergic cell dysfunction in PD.

Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

“…This resulted in parkin S-nitrosylation up to 3 h of treatment followed by denitrosylation at time points when the NO level was no longer increased. In accordance with our previous data showing the progressive long-term rise of in the cytosolic Ca 2+ in ASN-treated cells [33], we observed in this study that extracellular ASN induces long-lasting increase in NO level. Apart from deregulating NOS activity, extracellular ASN was demonstrated to exert its sustained action by elevation of nNOS expression [58].…”

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

“…), CDK5 overactivation (Czapski et al . ) and Ca 2+ dysregulation, beyond that of the modulation of plasma membrane receptors, channels, and pumps (Angelova et al . ; Ferreira et al .…”

“…Moreover, exogenous a-Syn affects cytoskeletal integrity via actin filaments stabilization (Bellani et al 2014), microtubule destabilization (Gassowska et al 2014), can promote defects in the axon elongation and guidance (Tilve et al 2015), as well as in growth and migration in developing neurons . Several other intracellular dysfunctions via in vitro extracellular a-Syn treatment have been revealed such as ROS elevation (Wang et al 2010), CDK5 overactivation (Czapski et al 2013) and Ca 2+ dysregulation, beyond that of the modulation of plasma membrane receptors, channels, and pumps (Angelova et al 2016;Ferreira et al 2017b).…”

The role of Ca2+ signaling in Parkinson's disease

“…The p35 activates Cdc5, a cyclin-dependent kinase that has a key role in neuronal development (Ko et al, 2001; Ohshima et al, 1996), axonal transport (Julien and Mushynski, 1998), synaptic activity (Rosales et al, 2000) and dopamine signaling (Chergui et al, 2004; Nishi et al, 2002). In MPTP-treated animals and in α-synuclein cell model systems, the activation of calpain leads to p35 being cleaved into its pathological form, p25, which results in the mislocalization and hyperactivation of Cdk5, and in DA neuronal loss in the mouse SNc (Czapski et al, 2013; Smith et al, 2006). p25 and overactive Cdk5 are detected in PD animal models (Qu et al, 2007; Smith et al, 2003) and in Lewy bodies from postmortem PD brains (Alvira et al, 2008; Takahashi et al, 2000).…”