Ruth Chalmers-Redman

Apoptosis in Parkinson's disease: signals for neuronal degradation.

Controversy has surrounded a role for apoptosis in the loss of neurons in Parkinsons disease (PD). Although a variety of evidence has supported an apoptotic contribution to PD neuronal loss particularly in the nigra, two factors have weighed against general acceptance: (1) limitations in the use of in situ 3′ end labeling techniques to demonstrate nuclear DNA cleavage; and (2) the insistence that a specific set of nuclear morphological features be present before apoptotic death could be declared. We first review the molecular events that underlie apoptotic nuclear degradation and the literature regarding the unreliability of 3′ DNA end labeling as a marker of apoptotic nuclear degradation. Recent findings regarding the multiple caspase‐dependent or caspase‐independent signaling pathways that mediate apoptotic nuclear degradation and determine the morphological features of apoptotic nuclear degradation are presented. The evidence shows that a single nuclear morphology is not sufficient to identify apoptosis and that a cytochrome c, pro–caspase 9, and caspase 3 pathways is operative in PD nigral apoptosis. BAX‐dependent increases in mitochondrial membrane permeability are responsible for the release of mitochondrial factors that signal for apoptotic degradation, and increased BAX levels have been found in a subset of PD nigral neurons. Studies using immunocytochemistry in PD postmortem nigra have begun to define the premitochondrial apoptosis signaling pathways in the disease. Two, possibly interdependent, pathways have been uncovered: (1) a p53–glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH)–BAX pathway; and (2) FAS receptor–FADD–caspase 8–BAX pathway. Based on the above, it seems unlikely that apoptosis does not contribute to PD neuronal loss, and the definition of the premitochondrial signaling pathways may allow for the development and testing of an apoptosis‐based PD therapy. Ann Neurol 2003;53 (suppl 3):S61–S72

Neuroprotection by deprenyl and other propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase B.

Summary. Deprenyl and other propargylamines are clinically beneficial in Parkinsons disease (PD). The benefits were thought to depend on monoamine oxidase B (MAO-B) inhibition. A large body of research has now shown that the propargylamines increase neuronal survival independently of MAO-B inhibition by interfering with apoptosis signaling pathways. The propargylamines bind to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The GAPDH binding is associated with decreased synthesis of pro-apoptotic proteins like BAX, c-JUN and GAPDH but increased synthesis of anti-apoptotic proteins like BCL-2, Cu-Zn superoxide dismutase and heat shock protein 70. Anti-apoptotic propargylamines that do not inhibit MAO-B are now in PD clinical trial.

Maintaining Mitochondrial Membrane Impermeability: An Opportunity for New Therapy in Glaucoma?

Apoptosis may contribute to retinal ganglion cell loss in glaucoma and glaucoma models. Recent research has suggested that mitochondrially dependent apoptosis signaling may contribute to apoptosis in a rat model of glaucoma involving chronic increases in intraocular pressure. In some forms of apoptosis, mitochondrially dependent signaling involves increases in mitochondrial membrane permeability and the mitochondrial release of factors that signal for cell degradation. Opening of a multi-protein, mitochondrial megapore is one factor that contributes to the increased permeability and some anti-apoptotic proteins, particularly BCL-2 and BCL-X(L), bind at the megapore and facilitate megapore closure and reduce increases in mitochondrial membrane permeability. Phosphorylated protein kinase B (Akt) serves as an integrator for cellular survival signals and facilitates the megapore actions of BCL-2 and BCL-X(L), which could protect retinal ganglion cells against insults that induce apoptosis. Several anti-apoptotic agents are being evaluated for use in glaucoma, including brimonidine and propargylamines, which oppose mitochondrially dependent apoptosis through pathways involving phosphorylated Akt.

Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer's disease: anti-apoptosis by alpha-2-adrenergic receptor activation.

Recent studies have suggested glaucomatous loss of retinal ganglion cells and their axons in Alzheimers disease. Amyloid beta peptides and phosphorylated tau protein have been implicated in the selective regional neuronal loss and protein accumulations characteristic of Alzheimers disease. Similar protein accumulations are not present on glaucomatous retinal ganglion cells. Neurons die in both Alzheimers disease and glaucoma by apoptosis, although the signaling pathways for neuronal degradation appear to differ in the two diseases. Alzheimers disease features a loss of locus ceruleus noradrenergic neurons, which send axon terminals to the brain regions suffering neuronal apoptosis and results in reductions in noradrenaline in those regions. Activation of alpha-2 adrenergic receptors reduces neuronal apoptosis, in part through a protein kinase B (Akt)-dependent signaling pathway. Loss of noradrenaline innervation facilitates neuronal apoptosis in Alzheimers disease models and may act similarly in glaucoma. Alpha-2 adrenergic receptor agonists offer the potential to slow the neuronal loss in both diseases by compensating for lost noradrenaline innervation.

Mitochondrial permeability in neuronal death: possible relevance to the pathogenesis of Parkinson's disease

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes catecholaminergic nerve cell loss and a syndrome similar to Parkinsons disease (PD). The metabolite of MPTP, MPP(+) (1-methyl-4-phenylpyridinium), decreases mitochondrial complex I activity similar to that in the PD nigra. Opening of a multi-protein, mitochondrial membrane pore constitutes a critical decisional event in some forms of apoptosis. We review recent findings showing that the permeability transition pore (PTP) opening caused by a decrease in the mitochondrial membrane potential (DeltaPsi(M)) contributes to MPP(+)-induced apoptosis. The reduction in DeltaPsi(M) appears to result from decreased proton pumping at complex I and therefore decreased complex I activity may also contribute to apoptosis in PD.