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.

Extracellular H+ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells.

Tyrosine hydroxylase catalyzes the rate-limiting step in the catecholamine biosynthetic pathway. Short-term TH activity is proposed to be regulated by the phosphorylation/dephosphorylation of regulatory domains Ser 40, 31, and/or 19 in response to membrane depolarization coupled increase in intracellular Ca2+. Here, we present in situ evidence to support that extracellular H+ ions ([H+]o) are an intracellular or extracellular Ca2+-independent novel signal for TH activation in catecholaminergic MN9D and PC12 cells. [H+]o-mediated TH activation is a short-term process coupled with a Na+-independent Cl-/HCO3- exchanger-mediated increase of intracellular hydrogen ions ([H+]i). While extracellular Ca2+ is not required for [H+]o-mediated TH activation, [H+]o does not increase the cytosolic Ca2+ levels in neuronal or non-neuronal cells in the presence or absence of extracellular Ca2+. Although [H+]o-mediated TH activation is associated with a significant increase in Ser 40 phosphorylation, major protein kinases proposed to be responsible for this process appear to be not involved. However, we have not been able to identify the protein kinase(s) involved in [H+]o-mediated phosphorylation of TH at present. Studies with a pan-phosphatase inhibitor, okadaic acid (OA), appear to indicate that the inhibition of phosphatase activities may not play a significant role in H+-mediated activation of TH. The relevance of these findings to the physiological TH activation mechanism and hypoxia, ischemia, and trauma-induced selective dopaminergic neural death is being discussed in this paper.

Visceral adipose tissue remodeling in pancreatic ductal adenocarcinoma cachexia: the role of activin A signaling.

Pancreatic ductal adenocarcinoma (PDAC) patients display distinct phenotypes of cachexia development, with either adipose tissue loss preceding skeletal muscle wasting or loss of only adipose tissue. Activin A levels were measured in serum and analyzed in tumor specimens of both a cohort of Stage IV PDAC patients and the genetically engineered KPC mouse model. Our data revealed that serum activin A levels were significantly elevated in Stage IV PDAC patients in comparison to age-matched non-cancer patients. Little is known about the role of activin A in adipose tissue wasting in the setting of PDAC cancer cachexia. We established a correlation between elevated activin A and remodeling of visceral adipose tissue. Atrophy and fibrosis of visceral adipose tissue was examined in omental adipose tissue of Stage IV PDAC patients and gonadal adipose tissue of an orthotopic mouse model of PDAC. Remarkably, white visceral adipose tissue from both PDAC patients and mice exhibited decreased adipocyte diameter and increased fibrotic deposition. Strikingly, expression of thermogenic marker UCP1 in visceral adipose tissues of PDAC patients and mice remained unchanged. Thus, we propose that activin A signaling could be relevant to the acceleration of visceral adipose tissue wasting in PDAC-associated cachexia.

Continuous treatment with cisplatin induces the oocyte death of primordial follicles without activation.

Chemotherapy directly or indirectly affects organs in a short-term or continuous manner. Endocrine organs are especially sensitive to cancer treatment, leading to concerns among patients regarding their quality of life afterward. Side effects to the ovary include damage to the ovarian reserve, resulting in follicle loss, endocrine hormone deficiency, and infertility. It has been previously demonstrated that continuous treatment with 2 mg/kg cisplatin for 15 days can activate primordial follicles, suggesting that the response in the oocytes of primordial follicles was dependent on cisplatin concentration and administration frequency. However, our results demonstrate that continuous treatment with 2 mg/kg cisplatin for 15 days leads to the same consequence as with the continuous treatment of 5 mg/kg cisplatin: the death of oocytes in primordial follicles without indication of activation. Moreover, animals co-injected with melatonin and cisplatin did not display any significant differences from those treated with cisplatin only contrary to the known results. 6-hydroxymelatonin, a metabolite of melatonin, could not prevent follicle destruction, implying that melatonin does not confer the protection of ovarian follicles, either directly or indirectly. Altogether, our data support that fertoprotectants against cisplatin must target molecules that control cell death pathways in the oocytes of primordial follicles.