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Gait disorders and postural instability, which are commonly observed in elderly patients with Parkinson disease (PD), respond poorly to dopaminergic agents used to treat other parkinsonian symptoms. The brain structures underlying gait disorders and falls in PD and aging remain to be characterized. Using functional MRI in healthy human subjects, we have shown here that activity of the mesencephalic locomotor region (MLR), which is composed of the pedunculopontine nucleus (PPN) and the adjacent cuneiform nucleus, was modulated by the speed of imagined gait, with faster imagined gait activating a discrete cluster within the MLR. Furthermore, the presence of gait disorders in patients with PD and in aged monkeys rendered parkinsonian by MPTP intoxication correlated with loss of PPN cholinergic neurons. Bilateral lesioning of the cholinergic part of the PPN induced gait and postural deficits in nondopaminergic lesioned monkeys. Our data therefore reveal that the cholinergic neurons of the PPN play a central role in controlling gait and posture and represent a possible target for pharmacological treatment of gait disorders in PD., Introduction Gait disorders and postural instability represent a major burden in the elderly population and are commonly observed in severe and advanced forms of Parkinson disease (PD; ref. 1). While [...]

Parkinson's disease is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Here we discuss a series of critical issues that we think researchers need to address to stand a better chance of solving the different challenges posed by this pathology., Parkinson's disease is often considered to be a simple pathological process that involves selective degeneration of the nigrostriatal pathway and a concomitant reduction in the striatal concentration of dopamine. This [...]

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that [CD8.sup.+] and [CD4.sup.+] T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1-/- and Tcrb-/- mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1-/- mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1-/- mice reconstituted with IFN-[gamma]--deficient splenocytes were not protected. These data indicate that T cell--mediated dopaminergic toxicity is almost exclusively arbitrated by [CD4.sup.+] T cells and requires the expression of FasL but not IFN[gamma]. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD., Introduction Parkinson disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine-containing neurons (DNs) in the substantia nigra (SN) pars compacta (SNpc). Except for rare genetic forms, PD [...]

Dopaminergic cell death in the substantia nigra (SN) is central to Parkinson's disease (PD), but the neurodegenerative mechanisms have not been completely elucidated. Iron accumulation in dopaminergic and glial cells in the SN of PD patients may contribute to the generation of oxidative stress, protein aggregation, and neuronal death. The mechanisms involved in iron accumulation also remain unclear. Here, we describe an increase in the expression of an isoform of the divalent metal transporter 1 (DMT1/Nramp2/ Slc11a2) in the SN of PD patients. Using the PD animal model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in mice, we showed that DMT1 expression increases in the ventral mesencephalon of intoxicated animals, concomitant with iron accumulation, oxidative stress, and dopaminergic cell loss. In addition, we report that a mutation in DMT1 that impairs iron transport protects rodents against parkinsonism-inducing neurotoxins MPTP and 6-hydroxydopamine. This study supports a critical role for DMT1 in iron-mediated neurodegeneration in PD. iron | oxidative stress | substantia nigra | MPTP | 6-hydroxydopamine

In multiple sclerosis (MS), oligodendrocyte and myelin destruction lead to demyelination with subsequent axonal loss. Experimental demyelination in rodents has highlighted the activation of the subventricular zone (SVZ) and the involvement of progenitor cells expressing the polysialylated form of neural cell adhesion molecule (PSA-NCAM) in the repair process. In this article, we studied the distribution of early [PSA-NCAM.sup.+] progenitors in the SVZ and MS lesions in human postmortem brains. Compared with controls, MS SVZ showed a 2- to 3-fold increase in cell density and proliferation, which correlated with enhanced numbers of [PSA-NCAM.sup.+] and glial fibrillary acidic protein-positive ([GFAP.sup.+]) cells. [PSA-NCAM.sup.+] progenitors mainly were [Sox9.sup.+], and a few expressed Sox10 and Olig2, markers of oligodendroglial specification. [PSA-NCAM.sup.+] progenitors expressing Sox10 and Olig2 also were detected in demyelinated MS lesions. In active and chronic active lesions, the number of [PSA-NCAM.sup.+] progenitors was 8-fold higher compared with chronic silent lesions, shadow plaques, and normal-appearing white matter. In active and chronic active lesions, [PSA-NCAM.sup.+] progenitors were more frequent in periventricular lesions (30-50%) than in lesions remote from the ventricular wall. These data indicate that, as in rodents, activation of gliogenesis in the SVZ occurs in MS and suggest the mobilization of SVZ-derived early glial progenitors to periventricular lesions, where they could give rise to oligodendrocyte precursors. These early glial progenitors could be a potential target for therapeutic strategies designed to promote myelin repair in MS. myelin | neural stem cells | remyelination | transcription factors | demyelination

The mechanisms leading to degeneration of dopaminergic neurons (DNs) in the substantia nigra of patients with Parkinson's disease (PD) are not completely understood. Here, we show, in the postmortem human tissue, that these neurons aberrantly express mitosis-associated proteins, including the E2F-1 transcription factor, and appear to duplicate their nuclear DNA. We further demonstrate that the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injected into mice and application of its active metaboiite 1-methyl-4-phenylpyridinium to mesencephalic cultures activate the retinoblastoma-E2F pathway in postmitotic DNs. We also find that cell death rather than mitotic division followed the toxin-induced replication of DNA, as determined by BrdU incorporation in DNs. In addition, blocking E2F-1 transcription protected cultured DNs against 1-methyl-4-phenylpyridinium toxicity. Finally, E2F-1-deficient mice were significantly more resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic cell death than their wild-type littermates. Altogether, BrdU incorporation in mature neurons and lack of evidence for newborn neurons argue against neuronal turnover in normal conditions or during pathological states in the substantia nigra. Instead, our results demonstrate that mitosis-like signals are activated in mature DNs in patients with PD and mediate neuronal death in experimental models of the disease. Inhibition of mitosis-like signals may therefore provide strategies for neuroprotection in PD. adult neurogenesis | neurodegeneration | retinoblastoma | apoptosis | dopamine

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopamine-containing neurons, but the molecular pathways underlying its pathogenesis remain uncertain. Here, we show that by eliminating c-Jun N-terminal kinases (JNKs) we can prevent neurodegeneration and improve motor function in an animal model of PD. First, we found that c-Jun is activated in dopaminergic neurons from PD patients and in the 1-methyl-4phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model of PD. Examination of various JNK-deficient mice shows that both JNK2 and JNK3, but not JNK1, are required for MPTP-induced c-Jun activation and dopaminergic cell demise. Furthermore, we have identified cyclooxygenase (COX) 2 as a molecular target of JNK activation and demonstrated that COX-2 is indispensable for MPTP-induced dopaminergic cell death. Our data revealed that JNK2- and JNK3-induced COX-2 may be a principle pathway responsible for neurodegeneration in PD.

The lactoferrin (Lf) receptors participates in the neuronal iron uptake in the substantia nigra pars compacta of parkinsonian patients causing iron gathering resulting in degradation of melanized nigral dopaminergic neurons during the disease. The expression of Lf receptor on blood-brain vasculature rises for Parkinson disease. The iron catalyzing the generation of free radicals is responsible for nerve cell death.

An in situ hybridization study was done on the decreased acetyltransferase mRNA expression in the nucleus basalis of Meynert in Alzheimer disease. It was shown that the level of expression of choline acetyltransferase mRNA in the nucleus basalis of Meynert from patients with Alzheimer disease was markedly decreased. These results suggest that the expression of choline acetyltransferase mRNA may be down-regulated in the cholinergic neurons identified in the nucleus basalis of Alzheimer patients.

Nitric oxide produced by glial cells may be responsible for destroying neurons in patients with Parkinson's disease. A drug that blocks the activity of the inducible form of nitric oxide synthase may prevent this destruction.

In the past, functional changes in the circuitry of the basal ganglia that occur in Parkinson's disease were primarily analyzed with electrophysiological and 2-deoxyglucose measurements. The increased activity of the subthalamic nucleus (STN) observed has been attributed to a reduction in inhibition mediated by the external segment of the globus pallidus (GPe), secondary to the loss of dopaminergic-neuron influence on D2-receptor-bearing striato-pallidal neurons. More recently, in situ hybridization studies of cytochrome oxidase subunit I have confirmed the overactivity of the STN in the parkinsonian state. In addition, this technique has provided evidence that the change in STN activity is owing not only to decreased inhibition from the GPe but to hyperactivity of excitatory inputs from the parafascicular nucleus of the thalamus and the pedunculopontine nucleus in the brainstem. Trends Neurosci. (2000) 23 (Suppl.), S78-S85