Intracellular signalling pathways in dopamine cell death and axonal degeneration

Abstract

The pathways of programmed cell death (PCD) are now understood in extraordinary detail at the molecular level. Although much evidence suggests that they are likely to play a role in Parkinson's disease (PD), the precise nature of that role remains unknown. Two pathways of cell death that are especially well characterized are cyclin-dependent kinase 5-mediated phosphorylation of myocyte enhancer factor 2 and the mitogen-activated protein kinase signalling cascade. Although blockade of these pathways in animals has achieved a truly remarkable degree of neuroprotection of the neuron cell soma, it has not achieved protection of axons. Thus, there is a need to explore beyond the canonical pathways of PCD and investigate mechanisms of axon destruction. We also need to move beyond the narrow classic concept that the mechanisms of PCD are activated exclusively 'downstream', following cellular injury. Studies in the genetics of PD suggest that in some forms of the disease, activation may be an early 'upstream' event. Additionally, recent observations suggest that cell death in some contexts may not be initiated by injury, but instead by a failure of intrinsic cell survival signalling. These new points of view offer new opportunities for molecular targeting.

Fig. 1

Resistance of neuron cell bodies, but not axons, to degeneration in JNK null mice. (a) The intra-striatal 6OHDA neurotoxin model induces apoptosis in SN dopamine neurons in wild-type mice. A typical example of an apoptotic profile, with characteristic chromatin clumps, is demonstrated by thionin counterstain in the inset. The homozygous jnk2 and jnk3 single null mutations suppressed apoptosis by 95 and 98%, respectively, and the homozygous jnk2/3 double null mutations completely abrogated apoptosis. (b) The homozygous jnk2/3 double null mutations provided virtually complete protection of SN dopamine neurons. Among wild-type (WT) mice, there was a 63% loss of dopamine neurons, typical for this model, whereas among jnk2/3 nulls, there was only a 4% decrease. Low-power photomicrographs of representative TH-immunostained SN sections from wild-type (top) and jnk2/3 nulls (bottom) following unilateral 6OHDA injection. (c) Homozygous jnk2/3 double null mice are not resistant to retrograde degeneration of nigrostriatal dopaminergic axons induced by intra-striatal 6OHDA. Following 6OHDA, there is a virtually complete loss of TH-positive fibre staining in homozygous jnk2/3 null mice, as in wild-type, throughout the striatum.

Fig. 2

Mediation of the extrinsic pathway of PCD by Fas. (a) The protein domain structure of Fas. The receptor has cysteine-rich domains (CRD) in the ligand binding region, characteristic of members of the TNF superfamily of receptors. There is a DD in the intracellular portion of the receptor. (b) Fas death signalling pathways. See text for details.

Fig. 3

GDNF signalling pathways. In some cellular contexts, GDNF signals independently of RET via interactions in cell membrane rafts with as yet unknown transmembrane proteins, leading to activation of Src-family kinases [see Trupp et al. (1999) and reviewed in Airaksinen and Saarma (2002)]. More often, GDNF signals through GFRα1 interactions with Ret. These interactions result in signalling through several candidate pathways, including PLCγ, Ras-ERKs and PI3K-Akt [modified from Trupp et al. (1999)].