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Many recent studies of the degeneration, neuroprotection and regeneration of CNS neurons have departed from previous dichotomous descriptions of neurons as either dead or alive. In this brief article aspects of neuronal health are examined by outlining ways to assess both neuronal resilience and vulnerability to common forms of structural brain insults. According to this theory of neuronal health, neurons exist in a dynamic equilibrium that spans a spectrum of cellular existence, constantly influenced by both extracellular physiological changes and intracellular mechanisms designed to react to external stimuli while maintaining structural integrity. The spectrum between particularly resilient and vulnerable neuronal states is illustrated by experiments in vivo that examine trophic and metabolic fluctuations influencing the likelihood of neuronal death after neuronal insults. Studies show that adult CNS neurons can be protected in vivo by trophic agents or other pharmacological interventions against structural and toxic damage. Conversely, low-level neuronal impairment due to genetic or physiological perturbations can predispose neurons to demise by insults that normally would not cause cell death. The experimental approaches described may help in the study of neuronal pathophysiology, and in investigations towards new treatments for the neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.

Development of noraderenergic (NA) neurons in the vertebrate brain is dependent on the homeodomain proteins Phox2a and 2b. Here, we show that Phox2a directly controls the NA identity by activating NA-synthesizing dopamine β-hydroxylase (DBH) gene. Single point mutations in the homeodomain of Phox2a resulted in a failure to transactivate the DBH promoter in vitro and resulted in the loss of NA neurons in vivo. In addition, injection of Phox2a-specific antisense oligonucleotide induced the loss of NA neurons in developing zebrafish. Phox2a and 2b activate the DBH promoter and bind to three domains (PBD1–3). PBD1 is composed of two overlapping sites with which monomers of Phox2a can interact. In contrast, PBD2 and 3 interact with the dimeric form of Phox2a. Mutations in three or four, but not one or two, of the binding sites completely abolished activation of the DBH promoter by Phox2a or 2b, while the conversion of PBD3 to a consensus motif (ATTA) improved the DBH promoter activity by > 10-fold. Taken together, these findings establish that Phox2a and 2b control the development of NA neurons in part by directly transactivating DBH transcription through interactions with four binding sites clustered in the proximal promoter. [ABSTRACT FROM AUTHOR]

Background: The etiology of Parkinson's disease (PD) remains elusive despite identification of several genetic mutations. It is more likely that multiple factors converge to give rise to PD than any single cause. Here we report that inflammation can trigger degeneration of dopamine (DA) neurons in an animal model of Parkinson's disease.Methods: We examined the effects of inflammation on the progressive 6-OHDA rat model of Parkinson's disease using immunohistochemistry, multiplex ELISA, and cell counting stereology.Results: We show that a non-toxic dose of lipopolysaccharide (LPS) induced secretion of cytokines and predisposed DA neurons to be more vulnerable to a subsequent low dose of 6-hydroxydopamine. Alterations in cytokines, prominently an increase in interleukin-1beta (IL-1beta), were identified as being potential mediators of this effect that was associated with activation of microglia. Administration of an interleukin-1 receptor antagonist resulted in significant reductions in tumor necrosis factor-alpha and interferon-gamma and attenuated the augmented loss of DA neurons caused by the LPS-induced sensitization to dopaminergic degeneration.Conclusion: These data provide insight into the etiology of PD and support a role for inflammation as a risk factor for the development of neurodegenerative disease. [ABSTRACT FROM AUTHOR]