Distinct neurological disorders with ATP1A3 mutations.
ABSTRACT Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases.
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ABSTRACT: Epilepsy genes deliver critical insights into the molecular control of brain synchronization and are revolutionizing our understanding and treatment of the disease. The epilepsy-associated genome is rapidly expanding, and two powerful complementary approaches, isolation of de novo exome variants in patients and targeted mutagenesis in model systems, account for the steep increase. In sheer number, the tally of genes linked to seizures will likely match that of cancer and exceed it in biological diversity. The proteins act within most intracellular compartments and span the molecular determinants of firing and wiring in the developing brain. Every facet of neurotransmission, from dendritic spine to exocytotic machinery, is in play, and defects of synaptic inhibition are over-represented. The contributions of somatic mutations and noncoding microRNAs are also being explored. The functional spectrum of established epilepsy genes and the arrival of rapid, precise technologies for genome editing now provide a robust scaffold to prioritize hypothesis-driven discovery and further populate this genetic proto-map. Although each gene identified offers translational potential to stratify patient care, the complexity of individual variation and covert actions of genetic modifiers may confound single-gene solutions for the clinical disorder. In vivo genetic deconstruction of epileptic networks, ex vivo validation of variant profiles in patient-derived induced pluripotent stem cells, in silico variant modeling and modifier gene discovery, now in their earliest stages, will help clarify individual patterns. Because seizures stand at the crossroads of all neuronal synchronization disorders in the developing and aging brain, the neurobiological analysis of epilepsy-associated genes provides an extraordinary gateway to new insights into higher cortical function.
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ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder that affects about 1.5% of the global population over 65 years of age. A hallmark feature of PD is the degeneration of the dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the consequent striatal DA deficiency. Yet, the pathogenesis of PD remains unclear. Despite tremendous growth in recent years in our knowledge of the molecular basis of PD and the molecular pathways of cell death, important questions remain, such as: 1) why are SNc cells especially vulnerable; 2) which mechanisms underlie progressive SNc cell loss; and 3) what do Lewy bodies or α-synuclein reveal about disease progression. Understanding the variable vulnerability of the dopaminergic neurons from the midbrain and the mechanisms whereby pathology becomes widespread are some of the primary objectives of research in PD. Animal models are the best tools to study the pathogenesis of PD. The identification of PD-related genes has led to the development of genetic PD models as an alternative to the classical toxin-based ones, but does the dopaminergic neuronal loss in actual animal models adequately recapitulate that of the human disease? The selection of a particular animal model is very important for the specific goals of the different experiments. In this review, we provide a summary of our current knowledge about the different in vivo models of PD that are used in relation to the vulnerability of the dopaminergic neurons in the midbrain in the pathogenesis of PD.Frontiers in Neuroanatomy 12/2014; 8. DOI:10.3389/fnana.2014.00155 · 4.18 Impact Factor
Article: Molecular mechanisms of epilepsy.[Show abstract] [Hide abstract]
ABSTRACT: Decades of experimental work have established an imbalance of excitation and inhibition as the leading mechanism of the transition from normal brain function to seizure. In epilepsy, these transitions are rare and abrupt. Transition processes incorporating positive feedback, such as activity-dependent disinhibition, could provide these uncommon timing features. A rapidly expanding array of genetic etiologies will help delineate the molecular mechanism(s). This delineation will entail quite a bit of cell biology. The genes discovered so far are more remarkable for their diversity than their similarities.