Neuroprotection of Parkin against apoptosis is independent of inclusion body formation

Abstract

Loss-of-function mutations in the parkin gene are known to result in autosomal recessive juvenile parkinsonism, which causes selective degeneration of nigrostriatal dopaminergic neurons in the absence of Lewy bodies. Here, we show that overexpression of parkin protects PC12 cells from neurotoxin of the proteasome inhibitor lactacystin and increases the accumulation of ubiquitin-protein conjugates and the formation of ubiquitin-positive inclusions induced by lactacystin. However, the protective effect of parkin against lactacystin-induced apoptosis is not associated with its ability to promote the formation of ubiquitinated inclusions. It is likely that Lewy body formation may be only a compensatory mechanism of dopaminergic neurons attempting to counteract toxicity, and not the ultimate cause of neuronal death.

Parkin and PINK1 functions in oxidative stress and neurodegeneration

“…Increased expression of Parkin protects against cell death induced by various stress conditions, such as mitochondrial stress, endoplasmic reticulum stress, excitotoxicity, and proteotoxic stress (Imai et al 2000; Petrucelli et al 2002; Darios et al 2003; Staropoli et al 2003; Higashi et al 2004; Jiang et al 2004; Muqit et al 2004; Yang et al 2005; Rosen et al 2006; Fett et al 2010). Parkin overexpression also has been shown to protect against nigral dopamine neuron loss in animal models of PD (Lo Bianco et al 2004; Vercammen et al 2006; Ulusoy and Kirik 2008; Bian et al 2012).…”

“…Parkin gene expression is upregulated under cellular stress, and transcription factors such as ATF4 and p53 can increase Parkin expression, whereas c-Jun and N-myc act as transcriptional repressors of Parkin (West et al 2004; Bouman et al 2011; Zhang et al 2011). Parkin also has been found to regulate several cell viability pathways including JNK, PI3K and NF-κB signaling, p53 transcriptional activity, and Bax activation (Cha et al 2005; Yang et al 2005; Henn et al 2007; Hasegawa et al 2008; da Costa et al 2009; Sha et al 2010; Johnson et al 2012a)…”

Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity

“…A decrease in parkin function leads to toxic accumulation of unwanted proteins and has been implicated in the etiology of various neurodegenerative disorders, including PD (Buneeva and Medvedev, 2006, Lim, 2007, Olzmann, et al, 2008). Conversely, overexpression of parkin protects DA neurons against a variety of cellular insults in vitro and in vivo , most importantly against those involved in mediating METH neurotoxicity, such as DA-induced oxidative stress, inhibition of mitochondrial function, and impairment of the proteasome (Darios, et al, 2003, Jiang, et al, 2012, Jiang, et al, 2004, Kirik and Bjorklund, 2005, Lo Bianco, et al, 2004, Oluwatosin-Chigbu, et al, 2003, Petrucelli, et al, 2002, Yang, et al, 2005, Yang, et al, 2011). These findings suggest the importance of parkin in the functioning and maintenance of DA neurons.…”

Parkin- An E3 Ubiquitin Ligase with Multiple Substrates

“…Furthermore, parkin protects against toxicity mediated by α-synuclein over-expression [22] and promotes the formation of ubiquitin positive inclusions when inhibiting the proteasome [23]. It has thus been proposed that LB formation is a protective response to toxic insults, rather than the primary cause to neuronal cell death, and that this process requires parkin activity.…”

“…Thus, parkin is regulating cellular proliferation by association with several important cell cycle regulatory molecules. Indeed parkin has been shown to exhibit tumour suppressor effects [23,47]. The link between cancer and parkin may also be related to the destabilization of cell proliferating mechanisms through the substrates mentioned above.…”