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 + and CD4 + 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-γ-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4 + T cells and requires the expression of FasL but not IFNγ. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.

Dopaminergic cell death in the substantia nigra (SN) is central toParkinson'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 P arkinson's disease (PD) is the most frequent neurodegenerative movement disorder worldwide. It is characterized by a preferential degeneration of dopaminergic neurons (DNs) in the substantia nigra pars compacta (SNpc) and the presence of proteinaceous cytoplasmic inclusions, called Lewy bodies, in the remaining DNs (1). Apart from rare, inherited forms of the disease, the etiology of PD remains unknown. Nevertheless, it seems clear that aging, mitochondrial dysfunction, inflammation, and oxidative imbalance are among the factors contributing to its pathophysiology.A rise in iron content localized in glial cells and DNs of the SNpc has been reported in patients with PD (2, 3). This increase of iron is thought to contribute to DN cell death by catalyzing the production of hydroxyl radicals from hydrogen peroxide, a byproduct in dopamine catabolism, and by promoting fibril formation of ␣-synuclein, the most abundant component of Lewy bodies (4). Neuroprotection achieved by pharmacological or genetic chelation of iron in animal models of PD supports the role of iron in neuronal degeneration in PD (5). Yet, the mechanisms underlying the iron increase have not been elucidated. Transferrin-bound iron (TBI) can be incorporated into cells by an endocytotic process, which is initiated by transferrin receptor 1 (TfR1) ligand binding. Following translocation to early endosomes, iron dissociates from transferrin and is transported to the cytoplasm or directly to the mitochondria. In the brain, iron uptake mediated by TfR participates in iron transport through the blood-brain barrier (6), and the density of TBI-binding sites correlates well with the regional distribution of TfR expression on the luminal surface of endothelial cells. However, TBI-binding sites and TfR expression only loosely correlate with the final steady-state distribution of iron (7). Moreover, TBI-binding sites are decreased in nu...

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 metabolite 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

Engrailed also confers in vivo protection against 6-hydroxydopamine and α-synuclein-A30P.Finally, the unilateral infusion of Engrailed into the midbrain increases striatal dopamine content resulting in contralateral amphetamine-induced turning. Therefore, Engrailed is both a

Among the pathogenic processes contributing to dopaminergic neuron (DN) death in Parkinson disease (PD), evidence points to non-cell-autonomous mechanisms, particularly chronic inflammation mounted by activated microglia. Yet little is known about endogenous regulatory processes that determine microglial actions in pathological states. We examined the role of glucocorticoid receptors (GRs), activated by glucocorticoids released in response to stress and known to regulate inflammation, in DN survival. Overall GR level was decreased in substantia nigra of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. GR changes, specifically in the microglia after MPTP treatment, revealed a rapid augmentation in the number of microglia displaying nuclear localization of GR. Mice with selective inactivation of the GR gene in macrophages/microglia (GR LysMCre ) but not in DNs (GR DATCre ) showed increased loss of DNs after MPTP intoxication. This DN loss in GR LysMCre mice was not prevented by corticosterone treatment, in contrast to the protection observed in control littermates. Moreover, absence of microglial GRs augmented microglial reactivity and led to their persistent activation. Analysis of inflammatory genes revealed an up-regulation of Toll-like receptors (TLRs) by MPTP treatment, particularly TLR9, the level of which was high in postmortem parkinsonian brains. The regulatory control of GR was reflected by higher expression of proinflammatory genes (e.g., TNF-α) with a concomitant decrease in anti-inflammatory genes (e.g., IL-1R2) in GR LysMCre mice. Indeed, in GR LysMCre mice, alterations in phosphorylated NF-κB levels indicated its protracted activation. Together, our data indicate that GR is important in curtailing microglial reactivity, and its deregulation in PD could lead to sustained inflammation-mediated DN injury.

A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia.

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Regulated intramembrane proteolysis by ␥-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different ␥-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-␥-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-␥-secretase. We demonstrate here that the Aph1B/C-␥-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level we find accumulation of Nrg1 fragments in the brain of Aph1BC ؊/؊ mice. Our observations gain clinical relevance by the demonstration that a Val-to-Leu mutation in the Nrg1 transmembrane domain, associated with increased risk for schizophrenia, affects ␥-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders.Alzheimer's ͉ knockout ͉ schizophrenia ͉ presenilin ͉ prepulse inhibition