On the Role of Aminochrome in Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Parkinson's Disease

摘要

The identity of what triggers the loss of dopaminergic neurons containing neuromelanin in Parkinson's disease (PD) is still unknown. Fifty years since its introduction in PD therapy, L-dopa is still the gold-standard drug despite severe side effects observed after 4 to 6 years of being treated with it. There are no new therapies that can halt or slow down the progression of the disease and much of the research efforts in this context have been destined to treat L-dopa-induced dyskinesia. There is huge concern about the difficulties that have been observed in the translation of successful preclinical results into clinical studies and new therapies in PD. The discovery of genes associated with familiar forms of PD has made an enormous input into basic research, which seeks to understand the degenerative process resulting in the loss of dopaminergic neurons in the nigrostriatal system. Several mechanisms have been suggested to be involved in the degeneration of nigrostriatal neurons in PD, including mitochondrial dysfunction, endoplasmic reticulum stress, lysosomal and proteasomal protein degradation dysfunction, the formation of neurotoxic alpha-synuclein (SNCA) oligomers, neuroinflammation, and oxidative stress. Mitochondrial Dysfunction The brain is completely dependent on chemical energy (ATP) in order to perform the release of neurotransmitters such as dopamine. Therefore, the existence of functional mitochondria is essential to the performed role of a dopaminergic neuron, i.e., to release dopamine. Postmortem brains with PD presented a deficiency in Complex I activity (Shapira et al., 1990 ; Esteves et al., 2011 ). Reduced Complex I activity in platelet mitochondria, purified from patients with idiopathic PD, has been observed (Esteves et al., 2011 ). CHCHD2 mutation in PD patient fibroblasts reduces oxidative phosphorylation in Complexes I and IV and induces fragmentation of the mitochondrial reticular morphology (Lee et al., 2018 ). A meta-analysis supports the deficit in Complexes I and IV in the case of peripheral blood, the frontal cortex, the cerebellum and the substantia nigra in PD (Holper et al., 2018 ). Analysis of mitochondria morphology in PD samples compared to controls revealed a significant decrease in the number of healthy mitochondria per cell. Several genes associated with familial forms of PD (PINK-1, DJ-1, Parkin, HTRA2) are linked to mitochondrial impairment (Larsen et al., 2018 ). Parkinson's disease, associated with vacuolar protein sorting 35 mutation, affects Complex I activity (Zhou et al., 2017 ). PINK1 and DJ-1 mutation induce energetic inefficiency (Lopez-Fabuel et al., 2017 ). SNCA induces mitochondrial dysfunction (Devi et al., 2008 ; Chinta et al., 2010 ; Nakamura et al., 2011 ; Martínez et al., 2018 ). Endoplasmic Reticulum Stress Endoplasmic reticulum is involved in secretory protein translocation and the quality control of secretory protein folding. Misfolded or unfolded proteins in the lumen accumulate under endoplasmic reticulum stress, which causing an integrated adaptive response identified as the unfolded protein response (UPR), which seeks to restore proteostasis within the secretory pathway (Cabral-Miranda and Hetz, 2018 ). The UPR activation markers, phosphorylated eukaryotic initiation factor 2alpha and phosphorylated pancreatic endoplasmic reticulum kinase, were detected in dopaminergic neurons containing neuromelanin in the substantia nigra of PD patients. Interestingly, phosphorylated pancreatic endoplasmic reticulum kinase was colocalized with an increased level of SNCA (Hoozemans et al., 2007 ). Neuropathological analysis of PD postmortem brain tissue revealed that pIRE1α is expressed within neurons containing elevated levels of α-synuclein or Lewy bodies (Heman-Ackah et al., 2017 ). SNCA triggers endoplasmic reticulum stress via the protein kinase RNA-like endoplasmic reticulum kinase/eukaryotic translation initiation factor 2α signaling pathway (Liu et al., 2018 ). N370S mutation and β-glucocerebrosidase-1 retention within the endoplasmic reticulum induce endoplasmic reticulum stress activation, triggering UPR and Golgi apparatus fragmentation (García-Sanz et al., 2017 ). It has been reported that endoplasmic reticulum stress activates the chaperone-mediated autophagy pathway via an EIF2AK3/PERK-MAP2K4/MKK4-MAPK14/p38-dependent manner (Li et al., 2018 ). Dopamine Oxidation and Parkinson's Disease One of the most characteristic features of the pathology of PD, which results in the onset of motor symptoms, is the massive loss of dopaminergic neurons containing neuromelanin in the nigrostriatal system. As mentioned before, several mechanisms, including mitochondrial dysfunction and endoplasmic reticulum stress, have been proposed as being involved in the degeneration of the nigrostriatal neurons in PD, but the question concerns what triggers these mechanisms in dopaminergic neurons containing neuromelanin. Many times, it has been suggested that the involve