Abnormal accumulation of the presynaptic protein alpha-synuclein has recently been implicated in the pathogenesis of Alzheimer's and Parkinson's diseases. Because neurodegeneration in these conditions might be associated with mitochondrial dysfunction and oxidative stress, the effects of alpha-synuclein were investigated in a hypothalamic neuronal cell line (GT1-7). alpha-Synuclein overexpression in these cells resulted in formation of alpha-synuclein-immunopositive inclusion-like structures and mitochondrial alterations accompanied by increased levels of free radicals and decreased secretion of gonadotropin-releasing hormone. These alterations were ameliorated by pretreatment with anti-oxidants such as vitamin E. Taken together these results suggest that abnormal accumulation of alpha-synuclein could lead to mitochondrial alterations that may result in oxidative stress and, eventually, cell death.

␣-Synuclein is a major component of aggregates forming amyloid-like fibrils in diseases with Lewy bodies and other neurodegenerative disorders, yet the mechanism by which ␣-synuclein is intracellularly aggregated during neurodegeneration is poorly understood. Recent studies suggest that oxidative stress reactions might contribute to abnormal aggregation of this molecule. In this context, the main objective of the present study was to determine the potential role of the heme protein cytochrome c in ␣-synuclein aggregation. When recombinant ␣-synuclein was coincubated with cytochrome c/hydrogen peroxide, ␣-synuclein was concomitantly induced to be aggregated. This process was blocked by antioxidant agents such as N-acetyl-L-cysteine. Hemin/ hydrogen peroxide similarly induced aggregation of ␣-synuclein, and both cytochrome c/hydrogen peroxideand hemin/hydrogen peroxide-induced aggregation of ␣-synuclein was partially inhibited by treatment with iron chelator deferoxisamine. This indicates that ironcatalyzed oxidative reaction mediated by cytochrome c/hydrogen peroxide might be critically involved in promoting ␣-synuclein aggregation. Furthermore, double labeling studies for cytochrome c/␣-synuclein showed that they were colocalized in Lewy bodies of patients with Parkinson's disease.Taken together, these results suggest that cytochrome c, a well known electron transfer, and mediator of apoptotic cell death may be involved in the oxidative stressinduced aggregation of ␣-synuclein in Parkinson's disease and related disorders.

The expression of ␣-synuclein, a synaptic molecule implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Lewy body disease is increased upon injury to the nervous system, indicating that it might play a role in regeneration and plasticity; however, the mechanisms are unclear. Because c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, plays an important role in stress response, the main objective of the present study was to better understand the involvement of this pathway in the signaling responses associated with resistance to injury in cells expressing ␣-synuclein. Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD) 1 are characterized by selective neuronal and synaptic damage in cortical and subcortical regions resulting in cognitive and motor impairment (1). The mechanisms leading to neurodegeneration in these disorders are unclear; however, recent studies suggest that abnormal aggregation of misfolded neuronal proteins might play a central role (2, 3). Although in Alzheimer's disease intracellular (4, 5) and extracellular aggregation of amyloid ␤-protein (5) has been implicated in PD, intraneuronal aggregation of misfolded ␣-synuclein (6 -8) has been suggested to be involved in the pathogenesis of the neurodegenerative process. In supporting a role of misfolded ␣-synuclein in the pathogenesis of PD, previous studies show that missense mutations that accelerates ␣-synuclein aggregation (9) are associated with familial PD (10, 11). Furthermore, Lewy bodies that are intraneuronal inclusions found in patients with parkinsonism are primarily composed of misfolded ␣-synuclein (6 -8), and overexpression of ␣-synuclein in transgenic mice (12) and Drosophila (13) resulted in Lewy body-like formation associated with degeneration of dopaminergic neurons. ␣-Synuclein is an abundant synaptic protein that is a member of the synuclein family of peptides that includes ␣-, ␤-, and ␥-synuclein as well as synoretin (14,15). The physiological roles of these proteins are unclear, although they might play an important role in neuroplasticity and in response to neuronal cell damage (14, 16). In support of this possibility, recent studies show that ␣-synuclein expression is increased in models of developmental-targeted injury (17,18). In this model, up-regulation of ␣-synuclein at the mRNA level is associated with an increase number of neurons expressing ␣-synuclein, and at the cellular level, ␣-synuclein is almost exclusively expressed in normal neurons rather than in apoptotic cells (18). Moreover, during development, ␣-synuclein expression is up-regulated (19), and the expression of this synaptic molecule is not further up-regulated during the period of natural cell death (17,18). In neuronal cell lines, overexpression of wild type ␣-synuclein protects against oxidative stress (20). In contrast, neuronal cell lines expressing ␣-synuclein that contains mutations (A30P and A53T) associated with familial Parkinsonism and...

A recent study suggested that neuroinflammation plays a major role in the pathogenesis of a number of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Although the precise mechanism is obscure, dysregulation of the signaling transduction pathway in microglia may enhance inflammation, leading to synaptic dysfunction and ultimately to neuronal cell death. The expression and function of the P2X7 receptor (P2X7R), an ATP-gated ion channel abundantly expressed in microglia in the brain, is significantly up-regulated in the postmortem brain of Alzheimer's disease patients and various neurodegenerative disease animal models. This supports the role of the P2X7R pathway in the progression of neurodegeneration. Blocking P2X7R using brilliant blue G, a P2X7R antagonist that can cross the blood-brain barrier, has been shown to result in the amelioration of neuropathology in various animal models. Taken together, these results raise the possibility that the P2X7R signaling pathway could be a therapeutic target for treating various neurodegenerative diseases.