The homeobox transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dose-dependent manner. Because of this requirement, the cells die by apoptosis when all four alleles of the Engrailed genes are genetically ablated (En1؊͞؊; En2؊͞؊). In the present study, we show that viable and fertile mice, heterozygous null for Engrailed-1 and homozygous null for Engrailed-2 (En1؉͞؊;En2؊͞؊), have an adult phenotype that resembles key pathological features of Parkinson's disease. Specifically, postnatal mutant mice exhibit a progressive degeneration of dopaminergic neurons in the substantia nigra during the first 3 mo of their lives, leading to diminished storage and release of dopamine in the caudate putamen, motor deficits similar to akinesia and bradykinesia, and a lower body weight. This genetic model may provide access to the molecular etiology for Parkinson's disease and could assist in the development of novel treatments for this neurodegenerative disorder.dopamine ͉ midbrain ͉ mouse mutant ͉ neurodegenerative disease ͉ substantia nigra M esencephalic dopaminergic (mesDA) neurons are the main source of dopamine in the mammalian central nervous system (1). They are located in three distinct nuclei, the substantia nigra pars compacta (SN), the ventral tegmentum (VTA), and the retrorubral field (RRF). Their main innervation targets are the basal ganglia, where they play a major role in controlling emotion, motivation, and motor behavior (2, 3), recognized by their involvement in schizophrenia, addiction, and most prominently in Parkinson's disease (PD; ref. 4). PD is a multisystemic degenerative disorder of the central and peripheral nervous systems. Its hallmark is the progressive degeneration of DA neurons in the SN. The clinical symptoms are resting tremor; muscular rigidity; postural instability; hyposomia; a positive response to the application of L-3,4-dihydroxyphenylalanine (L-DOPA); and the presence of cytoplasmatic inclusions (Lewy bodies) in postmortem brains (5). Additionally, PD patients are often characterized by weight loss starting before diagnosis and continuing with disease progression (6, 7).The homeodomain transcription factors Engrailed-1 and -2 (En1 and En2) are expressed by all mesDA neurons soon after differentiation and then continuously into adulthood. They are cell-autonomously and in a gene-dose-dependent manner required for the survival of this neuronal population, leading to the complete loss of the cells in mutant mice homozygous null for both genes (En1Ϫ͞Ϫ;En2Ϫ͞Ϫ; refs. 8 and 9). In their function as survival factors for mesDA neurons, the two genes are redundant and can compensate for each other (9, 10). The single-null mutants for either En1 (En1Ϫ͞Ϫ) or En2 (En2Ϫ͞Ϫ) show no significant alterations in the organization of the mesDA system at birth, but the mice with genotypes intermediate to the single and double mutants are distinctively different from each other. Whereas En1Ϫ͞Ϫ;En2ϩ͞Ϫ mice die at po...
Ischemic stroke is one of the most pervasive life-threatening neurological conditions for which there currently exists limited therapeutic intervention beyond prevention. As calcium-focused neuroprotective strategies have met with limited clinical success, it is imperative that alternative therapeutic targets be considered in the attempt to antagonize ischemic-mediated injury. As such, zinc, which is able to function both as a signaling mediator and neurotoxin, has been implicated in cerebral ischemia. While zinc was first purported to have a role in cerebral ischemia nearly twenty years ago, our understanding of how zinc mediates ischemic injury is still in its relative infancy. Within this review, we examine some of the studies by which zinc has exerted either neuroprotective or neurotoxic effects during global and focal cerebral ischemia.
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