Metabolic energy decline coupled dysregulation of catecholamine metabolism in physiologically highly active neurons: implications for selective neuronal death in Parkinson’s disease

Parkinson’s disease (PD) is an age-related irreversible neurodegenerative disease which is characterized as a progressively worsening involuntary movement disorder caused by the loss of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc). Two main pathophysiological features of PD are the accumulation of inclusion bodies in the affected neurons and the predominant loss of neuromelanin-containing DA neurons in substantia nigra pars compacta (SNpc) and noradrenergic (NE) neurons in locus coeruleus (LC). The inclusion bodies contain misfolded and aggregated α-synuclein (α-Syn) fibrils known as Lewy bodies. The etiology and pathogenic mechanisms of PD are complex, multi-dimensional and associated with a combination of environmental, genetic, and other age-related factors. Although individual factors associated with the pathogenic mechanisms of PD have been widely investigated, an integration of the findings to a unified causative mechanism has not been envisioned. Here we propose an integrated mechanism for the degeneration of DA neurons in SNpc and NE neurons in LC in PD, based on their unique high metabolic activity coupled elevated energy demand, using currently available experimental data. The proposed hypothetical mechanism is primarily based on the unique high metabolic activity coupled elevated energy demand of these neurons. We reason that the high vulnerability of a selective group of DA neurons in SNpc and NE neurons in LC in PD could be due to the cellular energy modulations. Such cellular energy modulations could induce dysregulation of DA and NE metabolism and perturbation of the redox active metal homeostasis (especially copper and iron) in these neurons

Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain

Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMAT’s role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H+ antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects

Mechanistic studies on non-heme monooxygenases : dopamine [beta]-monooxygenase and pseudomonas oleovorans monooxygenase system

Ph.D.Sheldon W. Ma

The inherent high vulnerability of dopaminergic neurons toward mitochondrial toxins may contribute to the etiology of Parkinson′s disease

Click on the DOI link to access the article (may not be free).Although the exact mechanism(s) of the degeneration of dopaminergic neurons in Parkinson's disease (PD) is not well understood, mitochondrial dysfunction is proposed to play a central role. This proposal is strongly strengthened by the findings that compromised mitochondrial functions and/or exposure to mitochondrial toxins such as rotenone, paraquat, or MPTP causes degeneration of the midbrain dopaminergic system and manifest symptoms similar to Parkinson's disease in primates and rodents (Goldman, 2014). In fact, the specific dopaminergic toxin MPTP is one of the most commonly used models in the mechanistic studies of environmental factors associated with the etiology of PD, particularly due to the availability of direct and unequivocal clinical and biochemical evidence from human and primate subjects