This page contains a Flash digital edition of a book.
Neurodegenerative Disease Parkinson’s Disease the protein α-synuclein,4 of neurotransmitter from synaptic terminals.5


which appears to have a role in the release One proposed mechanism


is α-synuclein-induced impairment of the ubiquitin-proteasomal system (UPS), resulting in protein accumulation and leading to cell degeneration.6 LBs are widely distributed in the brains of PD patients, including the SNc, raphe nucleus, locus ceruleus, pedunculopontine nucleus, dorsal motor nucleus of vagus, olfactory bulb, and some cortical structures.7


While the neuropathologic changes in PD are widespread and include a number of neurotransmitter pathways, the cardinal motor manifestations of the disease are clearly linked to the degeneration of the dopamine-producing cells in the SNc. Some of the postulated mechanisms of SNc cells’ death is oxidative stress and complex I mitochondrial dysfunction.8


A mitochondrial linkage is supported by the


recent advances in the knowledge of the genetic mutations associated with the rare familial forms of PD. Several of PD genes have a role in mitochondrial function. PINK1, DJ-1, and LRKK2 encode proteins that are localized to the surface or in the mitochondria.9–11


Rotenone, paraquat,


and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxins that produce animal models of parkinsonism are believed to work via mitochondrial complex I inhibition.10


It is believed that all Mitochondrial dysfunction leads


to the generation of reactive oxygen species (ROS), that are cytotoxic and can lead to the formation of LB-like intraneuronal filamentous inclusions, containing α-synuclein and ubiquitin.12,13


the above postulated pathogenic factors result in a common pathway of cell degeneration by mechanism of apoptosis.


Based on the postulated mechanisms of cell degeneration and preclinical data a number of clinical trials have been conducted or are underway aiming to attack various levels of the cascade of the neurodegenerative process. Tested agents targeted various potential mechanisms of PD pathogenesis including oxidative stress (eldepril, Vitamin E), mitochondrial dysfunction (CoQ10, ongoing studies of creatine), apoptotic mechanism of cell death (caspase inhibitors), antiexcitatory agents (riluzole), anti-inflammatory agents (minocycline), trophic factors, and others.14–23


So


far, none of the agents have demonstrated a positive effect on the course of the disease process. The reasons for negative results of the clinical trials are multifactorial, but one of them is likely a failure to address unique selective vulnerability of the cells in SNc.


The Physiologic Phenotype of Substantia Nigra Pars Compacta Dopaminergic Neurons Potentially Explains Selective Vulnerability Recent studies demonstrate that dopaminergic (DA) neurons in the SNc, as well as many neurons in other regions affected by PD, have a distinctive physiologic phenotype. They are slow and autonomous pacemakers, with broad action potentials.24–27


Although many neurons


in the brain generate autonomous activity, few have this physiologic phenotype. Most pacemakers have very short spikes and limit Ca2+ entry to a millisecond period around the spike. In contrast, SNc DA neurons have broad spikes and have membrane potential trajectories


that ensure that low threshold Ca2+ channels like those with a Cav1.3 subunit are open virtually all of the time. This continuous Ca2+ influx leads to oscillations in cytosolic Ca2+ concentration.24,25


This Ca2+ influx


distinguishes SNc DA neurons from DA neurons in the ventral tegmental area (VTA), which also are slow, broad action potential pacemakers.28


110


In contrast to SNc DA neurons, VTA DA neurons have a more modest vulnerability in PD.29


Substantia Nigra Pars Compacta Cells Pacemaking and Mitochondrial Oxidant Stress When neurons generate spikes, the transmembrane ionic gradients that enable this activity are dissipated. These gradients must be restored with ATP-dependent pumps and exchangers. Thus, sustained activity is energetically expensive. Ca2+ ions, because they must be rapidly sequestered or pumped back across the plasma membrane, could pose a particularly significant energetic burden. In neurons, this demand for ATP is met primarily by oxidative phosphorylation in mitochondria.30 Oxidative phosphorylation comes at a cost: the production of potentially damaging superoxide and reactive oxygen species.


Recent studies by our group have shown that Ca2+ entry through L-type channels elevates mitochondrial oxidant stress in SNc DA neurons.25 How this happens is not entirely understood. It does not appear to depend solely upon the energetic burden posed by Ca2+ entry and might involve altered mitochondrial respiratory control. This study also provided an important insight into how this Ca2+-dependent mitochondrial stress and genetic mutations associated with PD might interact to selectively increase the vulnerability of SNc DA neurons. Mutations in DJ-1 are associated with an early onset, recessive form of PD.10


In SNc DA neurons from mice lacking DJ-1, mitochondrial oxidant stress was significantly higher than in wild-type neurons. This was not simply a consequence of losing functional DJ-1 however, as neighbouring VTA DA neurons displayed no measurable stress. As in wild-type neurons, the oxidant stress was reversed by treatment with DHP channel antagonists. These results suggest that DJ-1 is activated only in response to oxidant stress and provide some measure of defense, an idea with broad experimental support.31


These data provide


a mechanism by which defects in a widely expressed gene can affect a small population of neurons. Furthermore, while elevated mitochondrial oxidant stress has long been hypothesized to play an important role in the etiology of PD, there has not been a coherent explanation for why SNc DA neurons—in particular—should be stressed. The physiologic phenotype of SNc DA neurons—pacemaking, broad action potentials, sustained opening of L-type Ca2+ channels, and the resulting mitochondrial oxidant stress—provides an explanation for selective vulnerability and, more importantly, establishes the target for potential neuroprotective interventions.


Indeed, antagonizing L-type Ca2+ channels is neuroprotective in toxin models. For example, pre-treatment of mesencephalic brain slices with isradipine, the most potent of the dihydropyridine (DHP) channel


Moreover, systemic administration of isradipine to mice at doses achieves serum concentrations in the same range as those found in humans following oral administration protects SNc DA neurons in both a chronic MPTP and acute 6-hydroxydopamine (6-OHDA) models.24,32


antagonists at L-type Ca2+ channels with the Cav1.3 subunit, significantly diminishes the damage to SNc DA neurons caused by the mitochondrial toxin rotenone.24


Although these channels participate in normal


pacemaking, they are not essential and antagonizing them with therapeutically relevant concentrations of dihydropyridine has no effect on the rest of the mouse behavior or phenotype.25


US NEUROLOGY


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100  |  Page 101  |  Page 102  |  Page 103  |  Page 104  |  Page 105  |  Page 106  |  Page 107  |  Page 108