Methamphetamine-induced neurotoxicity linked to ubiquitin-proteasome system dysfunction and autophagy-related changes that can be modulated by protein kinase C delta in dopaminergic neuronal cells

Abstract

A compromised protein degradation machinery has been implicated in methamphetamine (MA)-induced neurodegeneration. However, the signaling mechanisms that induce autophagy and UPS dysfunction are not well understood. The present study investigates the contributions of PKC delta (PKCδ) mediated signaling events in MA-induced autophagy, UPS dysfunction and cell death. Using an in vitro mesencephalic dopaminergic cell culture model, we demonstrate that MA-induced early induction of autophagy is associated with reduction in proteasomal function and concomitant dissipation of mitochondrial membrane potential (MMP), followed by significantly increased of PKCδ activation, caspase-3 activation, accumulation of ubiquitin positive aggregates and microtubule associated light chain-3 (LC3-II) levels. Interestingly, siRNA mediated knockdown of PKCδ or overexpression of cleavage resistant mutant of PKCδ dramatically reduced MA-induced autophagy, proteasomal function, and associated accumulation of ubiquitinated protein aggregates, which closely paralleled cell survival. Importantly, when autophagy was inhibited either pharmacologically (3-MA) or genetically (siRNA mediated silencing of LC3), the dopaminergic cells became sensitized to MA-induced apoptosis through caspase-3 activation. Conversely, overexpression of LC3 partially protected against MA-induced apoptotic cell death, suggesting a neuroprotective role for autophagy in MA-induced neurotoxicity. Notably, rat striatal tissue isolated from MA treated rats also exhibited elevated LC3-II, ubiquitinated protein levels, and PKCδ cleavage. Taken together, our data demonstrate that MA-induced autophagy serves as an adaptive strategy for inhibiting mitochondria mediated apoptotic cell death and degradation of aggregated proteins. Our results also suggest that the sustained activation of PKCδ leads to UPS dysfunction, resulting in the activation of caspase-3 mediated apoptotic cell death in the nigrostriatal dopaminergic system.

Cocaine induces astrocytosis through ER stress-mediated activation of autophagy

“…28 The cellular and molecular mechanism(s) leading to astrogliosis mediated by diverse agents as well as the related neuroinflammatory pathways that trigger astrogliosis are still areas of active investigation. While the role of drugs of abuse, such as morphine and methamphetamine, on induction of apoptosis, HIV disease progression, neuronal injury and neurodegeneration has been well established, [34][35][36][37][38][39] information in how the drugs influences astrogliosis and the role of autophagy in this process is very limited.…”

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

“…In this context, we recently demonstrated that methamphetamine (MA) induced dopaminergic neurotoxicity may be linked to concomitant impairment in mitochondrial function and autophagic flux (Kanthasamy et al, 2006; Lin et al, 2012). Additionally, recent reports implicate aberrant activation of c-Abl in the impaired autophagic clearance of α-synuclein and subsequent induction of dopaminergic neurotoxicity (Hebron et al, 2013a, b).…”

Role of proteolytic activation of protein kinase Cδ in the pathogenesis of prion disease

“…We have previously shown that protein kinase Cδ (PKCδ) is an oxidative stress-sensitive, pro-apoptotic kinase, which plays a causal role in apoptotic neuronal cell death. [12][13][14][15] We demonstrated that phosphorylation of tyrosine residue 311 and caspase-3-dependent proteolytic cleavage result in a persistent increase in the kinase activity, which promotes neuronal apoptosis. 13 Herein, we evaluate the role of PKCδ in prion neurotoxicity in ex vivo brain slice culture and in vivo experimental models of infectious prion disease.…”