The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, inactivation of Lmx1a and Lmx1b recreates cellular features observed in Parkinson's disease. We found that Lmx1a/b control the expression of key genes involved in mitochondrial functions, and their ablation results in impaired respiratory chain activity, increased oxidative stress, and mitochondrial DNA damage. Lmx1a/b deficiency caused axonal pathology characterized by α-synuclein + inclusions, followed by a progressive loss of dopaminergic neurons. These results reveal the key role of these transcription factors beyond the early developmental stages and provide mechanistic links between mitochondrial dysfunctions, α-synuclein aggregation, and the survival of dopaminergic neurons. M idbrain dopaminergic (mDA) neurons control key functions in the mammalian brain, including voluntary movement, associative learning, and motivated behaviors. Dysfunctions of the dopaminergic (DA) system underlie a wide variety of neurological and psychiatric disorders. The progressive and rather selective degeneration of mDA neurons is one of the principal pathological features of Parkinson's disease (PD) (1). In PD, neuronal loss is accompanied by the appearance of α-synucleinenriched intraneuronal inclusions called "Lewy bodies" and "Lewy neurites." The etiologies of PD remain unsolved, but mitochondrial dysfunction emerges as a central mechanism in inherited, sporadic, and toxin-induced PD (2).Specification of the subtype identities of mDA neurons begins during embryonic development. The combinatory activation of transcription factors (TFs) and their target genes allows the progenitors to mature progressively and terminally differentiate into postmitotic neuron subtypes. Tremendous efforts have been made to describe the complex spatiotemporal expression of TFs during mDA neuronal development (see refs. 3 and 4 for reviews). After mDA neuron maturation, a large number of developmentally expressed TFs remain active throughout adulthood. Our knowledge of the functional roles of these TFs in mature neurons remains rudimentary. Accumulating evidence shows that transcription factors including the nuclear receptor related 1 protein (Nurr1), En1, Pitx3, Otx2, and Foxa2, which are recognized for their role in the early development of mDA neurons, are also required for the maintenance of phenotypic neuronal identity in the adult (5).The LIM homeodomain genes Lmx1a/b are early determinants of the fate of mDA progenitors (6), and their actions are essential at each step of DA neuronal generation (7,8). The murine Lmx1a and Lmx1b proteins are closely related and share an overall amino acid identity of 64%, with 100% identity in their homeodomain and 67% and 83% identity in each LIM domain (9). These neuron...
Background:The application of low-intensity direct current electric fields has been experimentally used in the clinic to treat a number of brain disorders, predominantly using transcranial direct current stimulation approaches. However, the cellular and molecular changes induced by such treatment remain largely unknown.Methods:Here, we tested various intensities of direct current electric fields (0, 25, 50, and 100V/m) in a well-controlled in vitro environment in order to investigate the responses of neurons, microglia, and astrocytes to this type of stimulation. This included morphological assessments of the cells, viability, as well as shape and fiber outgrowth relative to the orientation of the direct current electric field. We also undertook enzyme-linked immunosorbent assays and western immunoblotting to identify which molecular pathways were affected by direct current electric fields.Results:In response to direct current electric field, neurons developed an elongated cell body shape with neurite outgrowth that was associated with a significant increase in growth associated protein-43. Fetal midbrain dopaminergic explants grown in a collagen gel matrix also showed a reorientation of their neurites towards the cathode. BV2 microglial cells adopted distinct morphological changes with an increase in cyclooxygenase-2 expression, but these were dependent on whether they had already been activated with lipopolysaccharide. Finally, astrocytes displayed elongated cell bodies with cellular filopodia that were oriented perpendicularly to the direct current electric field.Conclusion:We show that cells of the central nervous system can respond to direct current electric fields both in terms of their morphological shape and molecular expression of certain proteins, and this in turn can help us to begin understand the mechanisms underlying the clinical benefits of direct current electric field.
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