Impaired, Proteostasis leads to Degeneration of dopaminergic neurons of the nigrostriatal pathway

One of the critical functions in the long-lived cells such as neurons is the clearing system for the removal of the unfolded proteins. This function is provided by two major systems, the Ubiquitin Proteosome System (UPS) and the Autophagy-Lysosome Pathway (ALP) (Tai HC et al. 2008; Korolchuck VI et al. 2010 and Ravikumar B et al. 2010). Impaired proteostasis with formation of misfolded α-synuclein aggregates deregulates microtubule assembly and stability with reduction in axonal transport and impairment of mithocondrial trafficking and energy supply (Esposito et al. 2007; Chen et al. 2007; Borland et al. 2008; O’Malley 2010; Fujita et al. 2014; Weihofen et al. 2009).

Pathological consequences of these deregulated process include interference with the function of synapses, formation of toxic aggregates of proteins, impaired energy metabolism and turnover of mitochondria and chronic endoplasmic reticulum stress; all eventually leading to degeneration of DA neurons in the nigrostriatal pathway (Fujita et al. 2010, Shulman et al. 2011, Dauer et al. 2003, Orimo et al.2008, Raff et al. 2005; Schwarz 2015).

As described in the empirical support, a quantitative relationship has been established between chemical stressors inducing impaired proteostasis and loss of DA neurons of nigrostriatal pathway. The response-response relationship was evident in most of the studies and, where possible a relationship in dose-response could be also observed. A chronic dose regimen for the chemical stressor was necessary in most of the studies and this is confirming that a long lasting perturbation of the key event up is necessary to affect neuronal loss consistent with the presence of intracytoplasmatic inclusions. However, some inconsistency in the measurement of the endpoints relevant for impaired proteostasis were observed, probably because they also act as compensatory factors (Betarbet et al. 2006). The acute administration of MPTP (single injection of 30 mg/kg/ or 4 separate injections of 20 mg/kg) induced a transient inhibition of the UPS activity and neuronal loss but no intracytoplasmatic inclusions ie Lewy body were observed, supporting the temporal relationship among the two events (Fornai et al. 2005).

Neurotoxicity induced by continuous MPTP administration. (a) Representative tyrosine hydroxylase (TH)-stained sections of the substantia nigra from mice that were continuously treated for 28 days with control pump infusions or with infusions of 1, 5, or 30 mg MPTP/kg daily. (Scale bar, 600 μm.) (b and c) TH-positive cell counts in the substantia nigra (b) and semiquantitative densitometric measurements of the TH signal in striatum (c)(n = 10 mice per group). (d) Striatal monoamine levels in MPTP-treated mice (n = 10 mice per group). Asterisks indicate statistically significant differences (P < 0.05) of a sample compared to control (single asterisks) or to both the control and the lower MPTP dose (double asterisks).(From Fornai et al.2005).

Effect of an α-synuclein deletion on MPTP toxicity. (b) Uptake of [14C]2-DG in littermate wild-type and α-synuclein KO mice that were continuously infused for 7 days with control or MPTP (30 mg/kg daily) solution. Pictures display false-color autoradiograms. (c) Proteasome activity in control and α-synuclein KO mice continuously infused with MPTP (30 mg per kg of body weight daily). Proteasome activities in the substantia nigra are depicted as percent of control (means ± SEMs) as a function of time after beginning of the infusions (five mice per group). In a and c, asterisks indicate statistically significantly different values (P < 0.05) from controls. (From Fornai et al. 2005).

Multiple animal modeles have been used to mimic PD (Johnson et al. 2015). There are no sex restriction; however, susceptibility to MPTP increases with age in both non-human primates and mice (Rose et al.1993, Irwin et al. 1993, Ovadia et al. 1995).