Evidence for Apoptosis in Parkinsons Disease

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Parkinson's disease (PD) has been classically considered a predominantly environmentally related disorder with known etiologies, including MPTP toxin exposure, carbon monoxide exposure, postencephalitic related (1919 epidemic), manganese exposure, and other putative chemical exposures involving injury to mitochondrial complex I enzymes. Nevertheless, most cases are idiopathic without demonstrable etiology, and clearly some cases are genetically influenced. The knowledge that PD is related to progressive dopaminergic cell loss in the substantia nigra with symptomatology usually appearing at 80 to 90% cell depletion and the evidence connecting Parkin-sonism to environmental exposures has led to an oxidative stress theory for the pathogenesis of PD and an emphasis on apoptosis as a possible mechanism of cell loss.109110

Evidence for apoptosis in Parkinson's disease has been provided from both animal models and human material for the key cell population at risk, the dopaminergic neurons of the substantia nigra.111-118 In some experimental models of PD, there has been "mixed" evidence for classical cellular apoptosis with support for perhaps a variant of apoptotic cell death.111 It is important to point out that both in experimental animals and in human disease, cell death of dopaminergic neurons does occur in the setting of some amount of cellular inflammation and microglial response. This may indicate that cell death for some dopaminergic neurons may be relatively abrupt and proceed along the pathway of accidental or necrotic cell death with attendant inflammation. Likely, a continuum between apoptotic and necrotic cell death may occur, with the proportion depending on the magnitude and timing of the environmental toxin or stressor.23,24

A further issue in Parkinson's disease is the possible role of both endogenous L-dopa produced by the surviving dopaminergic neurons and exogenous L-dopa used in therapy as neurotoxins. A number of experiments have demonstrated the ability of L-dopa to induce apoptosis in cell culture.119-124 L-dopa synthesis and release is increased in surviving dopaminer-gic neurons to compensate for loss of neurons during the illness and may therefore contribute in a secondary manner to further injury. In addition, toxins affecting complex I in mitochondria, calcium stress, aging-related, or inherited mtDNA defects have been suggested as portals into apoptotic loss of dopaminergic neurons. 125-127 Protective therapy may be directed at mitochondrial or apoptotic mechanisms of cell injury and death.128,129

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