br Parkinson disease Idiopathic PD

Parkinson disease Idiopathic PD is a hypodopaminergic movement disorder of uncertain etiology that affects 3% of persons over age 65 (Dexter and Jenner, 2013). Cardinal signs of this common neurodegenerative condition include bradykinesia, rigidity, rest tremor and postural instability. Autonomic dysfunction, dementia and pre-motor manifestations (olfactory deficits, constipation, REM sleep behavior disorder and depression) may complete the clinical picture. Pathologically, PD is characterized by progressive attrition of DA neurons in the substantia nigra pars compacta, formation of α-synuclein-, ubiquitin- and tau-containing fibrillar inclusions (Lewy bodies and Lewy neurites) in the affected DA neurons and variable changes in other neurotransmitter systems (Lang, 2011). Excessive MG 149 iron deposition, oxidative stress, mitochondrial damage and mitophagy are ‘core’ neuropathological features common to PD and other aging-associated neurodegenerative conditions (Schipper and Song, 2015). Iron-mediated Fenton chemistry, pro-inflammatory cytokines, NO, electron transport infidelity, accelerated DA turnover (generating H2O2, ortho-semiquinones) and MPTP-like xenobiotics may promote oxidative damage in the PD basal ganglia (Jenner, 2003). Concerning the bioenergy deficits, there is evidence in human PD substantia nigra and relevant animal models of the disorder showing (i) increased mtDNA mutations in neurons and astroglia (Storm et al., 2002), (ii) diminished cytochrome subunit expression and complex I activity in neurons and glia (Hattori et al., 1991) and (iii) suppressed glucose utilization and enhanced lactate production using metabolic neuroimaging techniques (Bowen et al., 1995). PD-affected neural tissues may also feature excessive CA formation (Section 7.4) above and beyond the numbers typically encountered in normal aging (Auge et al., 2017; Pisa et al., 2016).
HO-1 and other neurodegenerative conditions In light of the remarkable responsiveness of HMOX1 to oxidative stress, one could safely surmise that highly variable patterns of neural HO-1 mRNA and protein expression would be encountered in the broad spectrum of adult and pediatric brain disorders featuring local or systemic perturbations of redox homeostasis (Schipper, 2004d). In many of these conditions, immunoreactive HO-1 protein is overexpressed in affected glial and/or neuronal compartments and co-localizes to the hallmark cytopathological features of the disease. Examples of the latter include co-staining of HO-1 with ballooned neurons in cases of corticobasal degeneration, Pick bodies in patients with frontotemporal dementia and neurofibrillary tangles in subjects with progressive supranuclear palsy and AD (Castellani et al., 1995). Furthermore, overexpression of Bach1, a negative transcriptional regulator of HO-1, has been observed in the brains of subjects with Down syndrome as well as mouse models of the disease. The latter findings were interpreted by the Butterfield group as indicating attenuation of the potentially neuroprotective effects of brain HO-1 in this condition (Di Domenico et al., 2015). On the basis of data reviewed in Section 5, we posit that the neural iron sequestration, oxidative substrate damage and mitochondrial insufficiency amply described in these and other late-onset human neurodegenerative disorders (Chang et al., 1995; Connor, 1997; Delisle et al., 2000; Reichmann and Riederer, 1994) are, in whole or in part, cytopathological sequelae of the aberrant HO-1 expression profiles. As such, rather than exacerbating Down syndrome pathology as suggested by Di Domenico et al., inhibition of HO-1 transcription by Bach1 hyper-expression (Di Domenico et al., 2015) may represent a neuroadaptive response to the disease.
Schizophrenia Schizophrenia is a hyperdopaminergic neurodevelopmental condition featuring disordered thought, affect and behavior that afflicts approximately 1% of the population world-wide. Neuropathological stigmata of the disease include altered regional brain volumes and cytoarchitectonics, ventriculomegaly, oxidative substrate modifications, mitochondrial damage (bioenergetic failure), macroautophagy, suppressed brain reelin and GAD67 expression and dysregulation of other genes and miRNAs implicated in neuronal proliferation, migration and differentiation (Bakhshi and Chance, 2015). An array of stressors acting during gestation and in the early postnatal period have been listed as risk factors or triggers of human neurodevelopmental illnesses including schizophrenia, autism and attention deficit-hyperactivity disorder. It has been proposed that diverse genetic and perinatal risk factors may converge upon limited neurodevelopmental trajectories to elicit schizophrenia and animal models of the disease (Brown, 2011). Under scrutiny in this regard are gestational exposure to various toxins, maternal psychotrauma and its impact on the hypothalamic-pituitary-adrenal axis, and maternal viral, bacterial or parasitic infection (Brown, 2011). Immune activation and production of pro-inflammatory cytokines have been heavily implicated as mediators of the dystrophic effects of maternal infection on the developing neuraxis (Meyer et al., 2008).