I bring you the wall of text that is my term paper (got an A on it :D)
Amphetamine Induced Changes in Protein Degradation and Apoptosis: PKCδ as a Central Regulator
Introduction:
Amphetamine (AMP) and methamphetamine (METH) are addictive, psychostimulant drugs of the amphetamine class, widely abused in many regions around the globe. It is estimated that there are 14-52 million amphetamine class stimulant users in the world, making the class the second widest used illicit drug in the world following cannabis (Granado et al., 2013). AMP and METH are thought to act in highly similar mechanisms so for the purpose of this paper will be treated as one and the same (Sulzer et al., 2005). Amphetamine class drugs are known to have several neurotoxic mechanisms, and recently protein kinase Cδ (PKCδ) has been implicated in METH induced changes in both the ubiquitin proteasome system (UPS) and autophagy in dopaminergic neurons (Yamatomo et al., 2010; Lin et al., 2012). Given the widespread use of these neurotoxic drugs the development of neuroprotective strategies are needed.
METH use has been shown to cause somewhat selective destruction of dopaminergic cells in humans, a pathophysiological trait often associated with Parkinson’s disease. Human METH addicts have been found at autopsy to have significant reductions of dopaminergic cells in the caudate and putamen, with larger losses seen in the former which is opposite the pattern seen in Parkinson’s disease (Moszczynska et al., 2004). This different pattern of cell losses may explain why motor disorders are not as common as cognitive disturbances in METH users (Moszczynska et al., 2004). Interestingly amphetamine treatment at low doses results in selective destruction of DA cell neuritis, and appears to spare the cell body which is lost in Parkinson’s disease (Ricaurte et al., 1982; Larsen et al., 2002; Fornai et al., 2003; Pasquali et al., 2008). Though previously, use of amphetamine class drugs was not thought to be a risk factor for Parkinson’s disease a growing body of evidence is now suggesting that may not be the case (Granado et al., 2013). Individuals hospitalized for (meth)amphetamine use have nearly a two-fold increase in Parkinson’s disease diagnoses later in life (Callaghan et al., 2010; Callaghan et al., 2012). Additionally, it has been estimated that 40% of METH users have neuropsychiatric abnormalities, highlighting the need for both neuroprotective and use-preventative treatments (Rippeth et al., 2004).
METH and AMP are thought to produce their stimulant and euphoric effects by acting as indirect agonists of dopamine (DA), noradrenalin (NE), and serotonin (5HT) receptors by both blocking the reuptake of these monoamines and inducing their release into the synaptic cleft via a non-exocytotic mechanism (Sulzer et al., 2005). It appears that amphetamine induced efflux of dopamine from DAT is dependent on phosphorylation of Thr(53) by PKCβ (Johnson et al., 2005; Foster et al., 2012). In addition, inducing efflux of cystolic dopamine via DAT. AMP also has been shown to increase cystolic DA via reversal or inhibition of VMAT2, a protein which sequesters cystolic NE and DA into vesicles. In addition, amphetamine has been shown to result in a temporary increase in the activity of tyrosine hydroxylase, the rate limiting enzyme in DA and NE synthesis, resulting in higher levels of cystolic dopamine (Larsen et al., 2002; Sulzer et al., 2005).
METH’s ability to somewhat selectively damage DA neurons is believed to stem from its ability to cause massively increased cystolic and extracellular DA levels, and in turn DA’s tendency to auto-oxidize producing free radicals including superoxide radicals, hydroxyl radicals, hydrogen peroxide and DA quinones (Pasquali et al., 2008; Krasnova & Cadet, 2009). Several “classical” factors have been implicated in amphetamine induced cell losses including: hyperthermia, production of reactive oxygen species (ROS) due to dopamine auto-oxidation and catabolism by monoamine oxidase (MAO), excitotoxicity, microglial activation, and the production of reactive nitrogen species (RNS) by nitric oxide synthase (NOS) (Yamatomo et al., 2010; Carvalho et al., 2012). Additionally, METH is classically known to possess several toxic effects selective to mitochondria, including inhibition of the electron transport chain complexes I, II-III, and IV leading to energy deficits as well as oxidative stress (Yamamoto et al, 2010). High dose METH is known to activate the intrinsic or mitochondrial death pathway begins with the loss of mitochondrial membrane potential resulting in permiabilization of the mitochondria and the release of cytochrome C, which binds to Apaf-1 forming a form a multi-protein apoptosome. This then activates procaspase-9 which in turn activates the effector caspase-3 which is essential for apoptosis (Kroemer et al., 2007; Lin et al., 2012).
Recent findings have suggested that METH also has significant effects on the two main protein degradation pathways in mammalian cells, the UPS and autophagy and that protein kinase Cδ (PKCδ) may play a key role (Pasquali et al., 2008; Lin et al., 2012). Various studies have implicated increased autophagy and decreased UPS activity in METH neurotoxicity, showing increased autophagic vacuoles as well as α-synuclein, ubiquitin, and parkin positive inclusions in the cytosol of nigral dopaminergic neurons.
PKCδ
Recent evidence points to PKCδ, a diaceylglycerol dependent serine/threonine kinase, as a key mediator of high dose METH induced protein clearance deficits and apoptosis(Lin et al., 2012). PKCδ is a ubiquitously expressed protein which has a complex role in the cell, acting as either a proapoptotic or antiapoptotic protein depending on its stimulus (Basu & Pal, 2010). PKCδ has also been found to be selectively upregulated and proteolytically cleaved following METH treatment relative to other PKC isoforms, in what is thought to be a ROS stimulated manner (Shin et al., 2012; Lin et al., 2012). Interestingly, PKCδ has a protective effect during early METH induced oxidative stress, activating the pro-survival PKD1, however it appears that with high levels of ROS for prolonged periods the antiapoptotic function is lost (Lin et al., 2012).
Despite PKCδ’s early protective role, it is believed that METH induced oxidative stress is results in several changes to PKCδ including phosphorylation of Tyr311 and Tyr332 both of which promote its cleavage by caspase-3 which removes the regulatory domain, resulting in a constitutively active fragment which promotes apoptosis (Kaul et al., 2005, Lu et al., 2007; Sun et al., 2008). PKCδ is links stress in many areas of the cell to apoptosis. As METH treatment results in rapid activation of ER stress associated proteins such as caspase-12 and calpain, ER stress is likely the one of the first steps in METH induced apoptosis (Jayanthi et al., 2004; Irie et al., 2011). Additionally, METH treatment was found to increase expression of ER protein chaperones suggesting increased protein mis-folding (Jayanthi et al., 2004). A potential caveat with the results reported by Jayanthi et al. (2004) which assumes caspase-12 activates caspase-3 is that most humans do not possess functional caspase-12, however the early release of Smac/DIABLO may be a potential cause of caspase-3 activation and subsequent PKCδ clevage (Xue et al., 2006).
PKCδ-catalytic fragment (PKCδ-CF) has been implicated in several proapoptosis actions such as targeting the antiapoptotic Bcl-2 protein Mcl-1 for degredation (Sitailo, Tibudan, and Denning., 2006). Additionally, as METH treatment causes endoplasmic reticulum (ER) stress, it may cause the translocation of PKCδ to the endoplasmic reticulum (ER) where it binds the ER tyrosine kinase c-abl which phosphorylates Tyr311, and subsequently translocates to the mitochondria where it triggers apoptosis (Lu et al., 2007; Qi & Mochly-Rosen, 2007; Irie et al., 2011).
As PKCδ does not appear to be required for normal development and function in Sprague-Dawley rats, and proteolytic cleavage of PKCδ by caspase-3 seems to commit a cell to apoptosis, it is an attractive target for pharmacological inhibition to address amphetamine induced protein degradation deficits (Sun et al., 2009; Shin et al., 2012; Lin et al., 2012). Several neuroprotective approaches have been researched to prevent the cleavage of PKCδ. Firstly, direct inhibition of caspase-3 cleavage of PKCδ via irreversible binding of the peptide Z-Asp(OMe)-Ile-Pro-Asp(OMe)-FMK to the caspase-3 cleavage site has showed promise in vitro, however it does not stop cleavage of other caspase-3 substrates (Kanthasamy et al., 2006). The polyphenol resveratrol has recently been reported to reduce caspase-3 activity and apoptosis in the N27 DA cell line at high micromolar concentrations. As its antioxidant properties alone cannot explain its protective effects it is likely that resveratrol modulates currently unidentified process that could be an attractive target for future research (Kanthasamy et al., 2011).
UPS Dysfunction
The UPS is an ATP dependent pathway for protein degradation, where soluble proteins in the nucleus and cytosol are targeted to the 26S proteasome by the addition of 76 amino acids long proteins known as ubiquitins (Hershko et al., 1980). Three levels of enzymes provide specificity to the system; E1 (ubiquitin-activating enzyme); E2 (ubiquitin-conjugating enzyme); and E3 (ubiquitin ligase) which presents the substrate to be ubiquitlated. For a protein to be degraded by the 26S proteasome system it requires at least four ubiquitilations at the lys48 position and partial unfolding, making large aggregates unlikely to be degraded (Korolchuk et al., 2010). UPS dysfunction is believed to occur in human METH users, as α-synuclein and ubiquitin immunoreactive inclusions have been identified in their nigral dopaminergic neurons post-mortem (Quin et al., 2005). The ability for METH to rapidly increase cystolic and extracellular DA levels has been implicated in the production of intracellular inclusions and dysfunction of the proteasome (Fornai et al., 2008; Won Um et al., 2010).
Extracellularly, overactivation of DA receptors on the plasma membrane via METH induced non-exocytotic DA results in rapid and reversible β-arrestin ubiquitilation and degredation of the dopamine receptor it has bound. β-arrestin is believed to play an important role in the early stages of ubiquitin positive inclusion formation in PC12 cells due to its early and rapid accumulation which may be too much for the inhibited UPS to process (Fornai et al., 2008).
Intracellulary, increased cystolic DA is believed to inhibit the proteasome system in several ways. ROS produced by DA auto-oxidation results in oxidative damage to parkin, a multifunctional E3 ubiquitin ligase, and its rapid conjugation with 4-hydroxy-2-nonenal a product of oxidized n-6 polyunsaturated fatty acids (Moszczynska & Yamamoto, 2011). Parkin directly enhances 26S activity by enhancing the binding between the 19S subunits, thus loss of parkin function will result in UPS deficits beyond its loss as an E3 ubiquitin ligase (Um et al., 2010).
Moszczynska & Yamamoto (2011) reported that use of a vitamin E, a lipophilic antioxidant prevented both loss of DA cell markers and inhibition of the 26S proteasome suggesting that antioxidants are a probable protective measure. Additionally, it has been reported that prostaglandin H synthase oxidizes DA into of DA quinones, and prostaglandin H synthase inhibitors such as the NSAID’s indomethacin, ibuprofen and naproxen may be effective in preventing the formation of DA (Miyazaki & Asanuma, 2008). Fornai et al.,(2008) found dopamine receptor antagonists to reduce the formations of inclusions in METH treated cells, by preventing agonism and subsequent β-arrestin binding.
Recently, it has been found that dysfunction of the UPS’s ability to degrade polyubiquinated proteins results in their preferential accumulation in the mitochondria. Interestingly, cells expressing mutant ubiquitin lacking Lys48 have robust protection against mitochondria initiated apoptosis (Pickart & Eddins, 2004; Sun et al., 2009). This accumulation of ubiquitnated proteins is believed to act in a pro-apoptotic manner through the mitochondrial pathways forming a feedback loop with caspase-3 activating PKCδ (Sun et al., 2008; Sun et al., 2009).
METH treatment rapidly causes dysfunctions of the proteasome system, thus preventing the degradation of NOS resulting in further protein modifications due to RNS production. METH is known to increase RNS production by indirectly increasing glutamate neurotransmission (Moszczynska & Yamamoto, 2010). Increased production of RNS and ROS may trigger further UPS dysfunction by activating PKCδ which like many other PKC kinases’ activity is increased by oxidative stress (Domenicotti et al., 2000). Lin et al. (2012) demonstrated that PKCδ plays a key role in METH induced changes in ubiquitin-proteasome system and autophagic activity.
Autophagy
Autophagy is a catabolic process in mammalian cells which is capable of digesting a wide variety of substrates by engulfing them in a double layered membrane forming an autophagosome. Autophagy is capable of removing aggregates, organelles, and proteasomal subunits (Cuervo et al.,1995; Korolchuk et al., 2010). Autophagosomes once formed are moved along microtubules where they fuse with lysosomes, and the contents within are digested by the liposomal enzymes (Iwata et al., 2005).
The role of autophagy in METH induced dopaminergic cell death has been controversial in the past, however Castino et al, (2008) showed that autophagy likely plays a protective role in PCL2 cells as inhibition of autophagy by 3-methyladenine, class III PI3K inhibitor, results in caspase dependent cell death.
Part of autophagy’s protective effect is believed to stem from increased clearance of protein aggregates such as α-synuclein, which has been observed to aggregate in response binding dopamine oxidation products (Conway et al., 2000; Norris et al., 2005; Castino et al., 2008). Expression of α-synuclein is increased by METH treatment as a presumably protective response, as α-synuclein may provide a buffer against oxidative stress by binding dopamine oxidation products (Machida et al., 2005). Additionally, wild type α-synuclien expression and aggregation has been found to be increased by ER stress(Jiang et al., 2012).Recently, α-synuclein has been implicated in repressing trascription of the key proapoptotic protein PKCδ by inhibiting NFκB and P300 histone deacetlyase activity (Jin et al., 2011). However, though METH may increase expression of neuroprotective α-synuclein the oxidative stress induced by METH’s may result in the formation of aggregates and fibrils which cannot be cleared by the proteasome system (Fornai et al, 2005).
Interestingly, Lin et al. (2012) reported increased mitophagy in response to METH treatment despite the reductions in the expression of parkin reported by Moszczynska & Yamamoto (2011). Parkin is well established to be a key mediator of mitophagy, the selective autophagy of damaged mitochondria which produce increased amounts of ROS (Joselin et al., 2012; Vincow et al., 2013). Vincow et al. (2013) also reported that the parkin-PINK1 pathway plays a key role in replacement of damaged respiratory chain complexes in mitochondria. METH induced oxidative damage to mitochondria can result in mitochondrial dysfunction, which normally can be removed or repaired in a parkin dependent pathway (Potula et al., 2010; Vincow et al., 2013). A potential explanation for the increase in mitophagy despite potential losses in parkin may be that the ~48% reduction in parkin in Sprague-Dawley rat DA neurons reported by Moszczynska & Yamamoto (2011) is insufficient to inhibit mitophagy in the N27 cell line used by Lin et al. (2012). This assumption agrees with Mortiboys et al. (2009) which found that a 50% knockdown of parkin expression in human fibroblasts did not impair mitophagy or mitochondrial function, but did result increased mitochondrial fission in response to complex I inhibition. By damaging both mitochondria and parkin METH may prevent the replacement of respiratory chain components potentially further increasing oxidative stress and targeting them for mitophagy (Vincow et al., 2013).
METH treatment results in changes in several of the factors involved in autophagy; Chin et al. (2009) found that METH treatment causes PKCδ activation which leads to downstream JNK1 mediated autophagy in response to acute but not prolonged hypoxia. Additionally METH induced autophagy has also been shown to be involve activation of the c-Jun-N-terminal kinase 1 (JNK 1) pathway and downstream phosphorylation of anti-apoptotic Bcl-2 inhibiting its binding to the BH3 domain of Beclin 1 in SK-N-SH cells (Nopparat et al., 2010). Beclin 1 is a class III PI3K which is important for the induction of autophagy which is inhibited by antiapoptotic Bcl-2 family proteins (Pattingre et al., 2005). Both Kongsuphol et al. (2009) and Lin et al. (2012) reported that the induction of autophagy by METH was correlated with a reduction in active S2448-phosphorylated mTOR, without a reduction in total amount of mTOR protein. METH induced inhibition of mTOR may be caused by oxidative stress and energy deficits due to mitochondrial inhibition (Burrows et al., 2000; Kongsuphol et al., 2009; Lin et al., 2012). Both Kongsuphol et al. (2009) and Nopparat et al., (2010) reported that melatonin, a potent lipophilic antioxidant prevented METH induced autophagic cell death, this suggest that the process is at least partly mediated by ROS, suggesting antioxidants may be a neuroprotective strategy.
Lin et al., (2012) was the first to report a METH induced reduction in LAMP-2, a protein involved in the fusion of autophagosomes and lysosomes, suggesting impaired autolysomal formation. This loss of LAMP-2 may be responsible for the large number of autophagosomes identified in METH treated cells, as they cannot be destroyed by lysosomal fusion (Eskelinen et al., 2002). The current mechanisms for the loss of LAMP-2 following METH treatment are unknown, however would be an interesting topic for future research (Lin et al., 2012). Lin et al. (2012) also identified for the first time a METH induced increase in p62/SQSTM1, a protein involved in the recognition of ubiquinated cargo in autophagy, suggesting an impairment of autophagic flux as p62/SQSTM1 is degraded in the process (Bjørkøy et al., 2009; Komatsu et al., 2007). Interestingly, excess p62 accumulation as a result of autophagy inhibition is believed to play a significant role in the inhibition of the UPS system by binding ubiquitin and forming proteasome resistant oligomers (Korolchuk et al., 2009; Korolchuk et al., 2010). The formation of p62-ubiquitin oligomers may play an important role in the inhibition of the proteasome system and upregulation of autophagy, by being a potential positive feedback loop.
Inhibition of the UPS can also lead to accumulation of p53 in the nucleus while depleting monoubiquitinated cystolic p53 further increasing autophagy (Tasdemir et al., 2004). Additionally, it appears that while autophagy can be upregulated in response to UPS inhibition in a histone deacetylase 6 dependent process, the UPS activity cannot be upregulated in response to inhibition of autophagy (Pandey et al., 2007). Taken together, these findings suggest that METH inhibits both autophagy and the UPS in a synergistic manner.
Conclusion
Amphetamine class drugs are the second most widely abused illicit drug, and also are know to produce neurotoxic effects in humans (Granado et al., 2013). Recent evidence has shown that PKCδ, autophagy, and the ubiquitin proteasome system are involved in their neurotoxic effects (Lin et al., 2012). As these drugs represent a significant health risk to a sizable portion of the population, research on neuroprotective strategies is needed.
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