The nigrostriatal DA pathway and PD

All About Parkinson's Disease

All About Parkinson's Disease By Lianna Marie

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In sporadic PD there is increasing evidence that mitochondrial dysfunction, with reduced formation of ATP and increased formation of reactive oxygen species (ROS) leading to oxidative damage, plays an important role in the pathogenesis (Dauer and Przedborski, 2003; Beal, 2000). Both genetic susceptibility factors and environmental factors such as toxins, virus infections and hypercaloric diet may be involved in the etiology (Barja, 2004; Fuente-Fernandez and Calne, 2002).

Braak et al. (2004) have made the discovery that PD may be a multisystem disorder, where projection neurons with unmyelinated or weakly myelinated axons are especially vulnerable. The nigrostriatal DA neurons represent such a type of neuron. In presymp-tomatic stages mainly the medulla oblongata with the dorsal motor nucleus of the vagus nerve and the olfactory bulb are affected shown inter alia with alfa synuclein immuno-reactivity, indicating a possible neuro-invasion by an unknown pathogen (Braak et al., 2003). It also seems possible however that these vulnerable neurons may be especially susceptible to mitochondrial dysfunction since there is high demand for ATP to make it possible for the Na/K ATPase to restore the resting membrane potential after each action potential depolarizing the entire axon as it travels long distances down to the terminals. The deficiencies in complex I activity in PD may also enhance the misfolding of proteins and their aggregation, resulting in abnormal protein-protein interactions (Agnati et al., 2005a), contributing to the neurodegeneration (protein conformational disorders). The ubiquitin-proteosomal pathway cannot cope with this increased demand for protein degradation, especially since this process is ATP dependent. The misfolding of proteins also takes place in the DA axons and terminals that may lead to interference with axoplasma flow that also is highly ATP dependent, explaining, for example, the swollen alfa-synuclein IR neurites found early in PD (Braak et al., 2004). These protein aggregates give rise to the Lewy bodies in PD.

There may be several reasons why, for example, certain DA nerve cells in the zona compacta, like those in the ventral and lateral parts, are more vulnerable to neurodegeneration in PD than other DA cells in the zona compacta. It may be that they belong to different types of trophic units (Agnati et al., 1995) and therefore can't receive the same trophic support from extracellular FGF-2 (Fuxe et al., 1996) and GDNF (Grondin et al., 2002). It may also be that the DA cells with highest vulnerability have lower amounts of, or different types of, ATP sensitive potassium channels (KATP) that are not as sensitive to metabolic stress. Therefore, they cannot spare sufficient amounts of neuronal energy as they cannot effectively shut down the firing of the DA cells in response to the reduced ATP/ADP ratio via opening of the K+ channels leading to hyperpolarization (see Liss and Roepner, 2001).

It is of importance that hydrogen peroxide (H2O2) can activate the sulfonylurea receptor 1 that contains KATP channels, causing glutamate dependent inhibition of striatal dopamine release (Avshalumov and Rice, 2003). This may be an additional reason why DA cells with these types of KATP channels, activated also by ROS, may show increased protection against PD (Liss and Roepner, 2001).

Based on the mitochondrial hypothesis of PD, it must be emphasized that the reduction of ATP signalling may be a significant factor in causing the degeneration of the nerve cells in PD, but this has not been previously discussed. Thus, ATP is known to be an extracellular activity dependent signalling molecule in neuron/glia communication

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Fig. 1. Schematic illustration of ATP as a volume transmission (VT) and wiring transmission (WT) signal, and as an intracellular and intra-inter mitochondrial signal

Fig. 1. Schematic illustration of ATP as a volume transmission (VT) and wiring transmission (WT) signal, and as an intracellular and intra-inter mitochondrial signal acting via many subtypes of P2x (ion channel coupled) and P2y (G protein coupled) receptors and may exert trophic actions (Fields and Stevens, 2000; Burnstock and Knight, 2004). As seen in Fig. 1, ATP can operate as a short-range volume transmission (VT) signal between neurons and glia while its metabolites ADP and adenosine (ADE) can operate as intermediate VT signals. ATP may also operate as a synaptic signal. Thus, ATP may be released from DA cells and dendrites as a transmitter, like DA.

Reduction of ATP as an intracellular signal can, as discussed, lead to the opening of KATP channels on the plasma membrane with hyperpolarization and reduction of the firing rate. As also illustrated, ATP can act as an intramitochondrial and intermitochondrial signal. Its reduction here activates mitochondrial ATP sensitive potassium channels, leading to depolarization and an increase of ATP synthesis, in this way affecting the set point of energy production (Busija et al., 2004). Taken together the combined actions on KATP channels by ATP reductions will allow a balance to develop between firing and

ATP synthesis (Fig. 2). If this energy balance is disrupted the nigrostriatal DA function wears off.

Such a disruption may be brought about if subtypes of ATP P2x receptors (see North, 2002) exist on the nigral DA nerve cells. These ATP receptors are permeable to small monovalent cations and certain subtypes to Ca ions. It is of significance that certain subtypes of P2x receptors may be activated by ROS, especially H2O2 and hydroxyl radicals, as demonstrated in vagal lung afferent fibres (Ruan et al., 2005) and such P2x receptors may be postulated to exist on DA nerve cells (Fig. 3). The resulting sodium influx will produce a depolarization of the DA cell since the Na/K-ATPase cannot maintain the ion gradient, and the KATP channels close upon depolarization (Bryan et al., 2004) and the inhibitory D2 autoreceptor activated inwardly rectifying K+ current mainly operate at resting membrane potential (Fig. 3). The most interesting P2x receptor relating to this hypothesis would be the P2x7 receptor, as it fails to desensitize and larger currents are found upon repeated application. After several

Fig. 2. Scheme of plasma membrane and mitochondrial KATP channel activation by ATP depletion leading to energy balance in conditions with high metabolic demands

Fig. 3. Hypothesis on the possible role of P2x receptors in nigral DA nerve cells as to their degeneration in PD. Due to mitochondrial dysfunction in PD, ROS may be formed thereby activating the P2x receptors together with ATP released from degenerating nerve cells and glial cells with influx of especially Na ions, leading to depolarization, since the Na/K ATPase cannot maintain the ion gradients. The KATP channels close as the membrane depolarizes and cannot act as a brake nor can the D2 autoreceptors that activate inwardly rectifying K+ channels operating close to the equilibrium membrane potential. The resulting high firing rate will cause a progressive ATP depletion of the DA neuron leading to cell death. Similar events may take place in other vulnerable neurons in PD and P2x receptors have been demonstrated in the dorsal motor nucleus of the vagus (Burnstock and Knight, 2004)

where the pathology begins (Braak et al., 2004)

Fig. 3. Hypothesis on the possible role of P2x receptors in nigral DA nerve cells as to their degeneration in PD. Due to mitochondrial dysfunction in PD, ROS may be formed thereby activating the P2x receptors together with ATP released from degenerating nerve cells and glial cells with influx of especially Na ions, leading to depolarization, since the Na/K ATPase cannot maintain the ion gradients. The KATP channels close as the membrane depolarizes and cannot act as a brake nor can the D2 autoreceptors that activate inwardly rectifying K+ channels operating close to the equilibrium membrane potential. The resulting high firing rate will cause a progressive ATP depletion of the DA neuron leading to cell death. Similar events may take place in other vulnerable neurons in PD and P2x receptors have been demonstrated in the dorsal motor nucleus of the vagus (Burnstock and Knight, 2004)

where the pathology begins (Braak et al., 2004)

seconds of P2x7 activation, permeability to larger organic cations increases. This may either be related to a dilation of the pore of the P2x7 channel or to the activation of a distinct channel protein (North, 2002). After prolonged agonist application, the P2x7 activation leads to membrane blebbing, seen as large hemispherical protrusions, and finally to cell death (North, 2002). The pore formation with influx of extracellular chloride ions seems to play a major role for the apoptotic cell death induced (Tsukimoto et al., 2005). Antagonists of P2x7 receptors are presently being developed against inflammatory processes (Baraldi et al., 2004).

Based on the present hypothesis it will be of substantial interest to study the distribution pattern of P2x and P2y receptors in the nigrostriatal DA pathway and its subsystems, as well as in the adjacent astroglia and micro-glia, and how the receptor distribution pattern may change in models of PD, and in PD with focus on P2x7 receptors. This approach may reveal new aspects of the mechanisms of neurodegeneration in the nigrostriatal DA neurons in PD, and initiate novel strategies for neuroprotective treatments of PD based on, for example, the development of P2x receptor antagonists.

Acknowledgements

This work has been supported by a grant from the Marianne and Marcus Wallenberg Foundation, by a grant from the Swedish Research Council, and a grant from the Sweden-South Africa International Research Partnership.

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