Syndromic autism spectrum disorders represent a group of childhood neurological conditions, typically associated with chromosomal abnormalities or mutations in a single gene. The discovery of their ...genetic causes has increased our understanding of the molecular pathways critical for normal cognitive and social development. Human studies have revealed that the brain is particularly sensitive to changes in dosage of various proteins from transcriptional and translational regulators to synaptic proteins. Investigations of these disorders in animals have shed light on previously unknown pathogenic mechanisms leading to the identification of potential targets for therapeutic intervention. The demonstration of reversibility of several phenotypes in adult mice is encouraging, and brings hope that with novel therapies, skills and functionality might improve in affected children and young adults. As new research reveals points of convergence between syndromic and nonsyndromic autism spectrum disorders, we believe there will be opportunities for shared therapeutics for this class of conditions.
The postnatal neurodevelopmental disorder Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2), a transcriptional repressor involved in chromatin ...remodeling and the modulation of RNA splicing.
MECP2 aberrations result in a constellation of neuropsychiatric abnormalities, whereby both loss of function and gain in
MECP2 dosage lead to similar neurological phenotypes. Recent studies demonstrate disease reversibility in RTT mouse models, suggesting that the neurological defects in
MECP2 disorders are not permanent. To investigate the potential for restoring neuronal function in RTT patients, it is essential to identify MeCP2 targets or modifiers of the phenotype that can be therapeutically modulated. Moreover, deciphering the molecular underpinnings of RTT is likely to contribute to the understanding of the pathogenesis of a broader class of neuropsychiatric disorders.
Inhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are ...heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non-overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors.
•Mecp2 loss in PV+ and SOM+ neurons leads to non-overlapping neurological phenotypes•Mecp2 deletion in PV+ neurons causes motor, sensory, memory, and social deficits•Mecp2 deletion in SOM+ neurons causes seizures and stereotypies
Inhibitory neurons are heterogeneous, but how individual subtypes contribute to behavior is unknown. Here, Ito-Ishida et al. show that dysfunction of the two most populous subtypes, PV+ and SOM+ neurons, cause distinct, non-overlapping behavioral phenotypes that recapitulate global Mecp2 loss.
This year marks the 50th anniversary of the publication of Andreas Rett’s report on 22 girls who developed a peculiar and devastating neurological disorder that later came to bear his name. On this ...occasion, we reflect on the progress that has occurred in understanding Rett Syndrome, development of potential treatments, and the ramifications that Rett research has had on the fields of neurobiology and genetics.
This year marks the 50th anniversary of the publication of Andreas Rett’s report on 22 girls who developed a peculiar and devastating neurological disorder that later came to bear his name. On this occasion, we reflect on the progress that has occurred in understanding Rett Syndrome, development of potential treatments, and the ramifications that Rett research has had on the fields of neurobiology and genetics.
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by degeneration of the substantia nigra pars compacta and by accumulation of α-synuclein in Lewy bodies. PD is caused by ...a combination of environmental factors and genetic variants. These variants range from highly penetrant Mendelian alleles to alleles that only modestly increase disease risk. Here, we review what is known about the genetics of PD. We also describe how PD genetics have solidified the role of endosomal, lysosomal, and mitochondrial dysfunction in PD pathophysiology. Finally, we highlight how all three pathways are affected by α-synuclein and how this knowledge may be harnessed for the development of disease-modifying therapeutics.
In this issue, a pair of studies (Levy et al. and Sanders et al.) identify several de novo copy-number variants that together account for 5%–8% of cases of simplex autism spectrum disorders. These ...studies suggest that several hundreds of loci are likely to contribute to the complex genetic heterogeneity of this group of disorders. An accompanying study in this issue (Gilman et al.), presents network analysis implicating these CNVs in neural processes related to synapse development, axon targeting, and neuron motility.
Trinucleotide repeat disorders Orr, Harry T; Zoghbi, Huda Y
Annual review of neuroscience,
01/2007, Letnik:
30
Journal Article
Recenzirano
The discovery that expansion of unstable repeats can cause a variety of neurological disorders has changed the landscape of disease-oriented research for several forms of mental retardation, ...Huntington disease, inherited ataxias, and muscular dystrophy. The dynamic nature of these mutations provided an explanation for the variable phenotype expressivity within a family. Beyond diagnosis and genetic counseling, the benefits from studying these disorders have been noted in both neurobiology and cell biology. Examples include insight about the role of translational control in synaptic plasticity, the role of RNA processing in the integrity of muscle and neuronal function, the importance of Fe-S-containing enzymes for cellular energy, and the dramatic effects of altering protein conformations on neuronal function and survival. It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets.
Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life before experiencing profound ...motor and cognitive decline
. At present there are no effective treatments for Rett syndrome, but we hypothesized that using the period of normal development to strengthen motor and memory skills might confer some benefit. Here we find, using a mouse model of Rett syndrome, that intensive training beginning in the presymptomatic period dramatically improves the performance of specific motor and memory tasks, and significantly delays the onset of symptoms. These benefits are not observed when the training begins after symptom onset. Markers of neuronal activity and chemogenetic manipulation reveal that task-specific neurons that are repeatedly activated during training develop more dendritic arbors and have better neurophysiological responses than those in untrained animals, thereby enhancing their functionality and delaying symptom onset. These results provide a rationale for genetic screening of newborns for Rett syndrome, as presymptomatic intervention might mitigate symptoms or delay their onset. Similar strategies should be studied for other childhood neurological disorders.
The discovery of the genetic causes of syndromic autism spectrum disorders and intellectual disabilities has greatly informed our understanding of the molecular pathways critical for normal synaptic ...function. The top-down approaches using human phenotypes and genetics helped identify causative genes and uncovered the broad spectrum of neuropsychiatric features that can result from various mutations in the same gene. Importantly, the human studies unveiled the exquisite sensitivity of cognitive function to precise levels of many diverse proteins. Bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets. Moreover, studies in model organisms showed that symptoms of these devastating disorders can be reversed, which brings hope that affected individuals might benefit from interventions even after symptoms set in. Scientists predict that insights gained from studying these rare syndromic disorders will have an impact on the more common nonsyndromic autism and mild cognitive deficits.
The X-linked gene encoding MECP2 is involved in two severe and complex neurodevelopmental disorders. Loss of function of the MeCP2 protein underlies Rett syndrome, whereas duplications of the MECP2 ...locus cause MECP2 duplication syndrome. Research on the mechanisms by which MeCP2 exerts effects on gene expression in neurons, studies of animal models bearing different disease-causing mutations, and more in-depth observations of clinical presentations have clarified some issues even as they have raised further questions. Yet there is enough evidence so far to suggest possible approaches to therapy for these two diseases that could go beyond attempting to address specific signs and symptoms (of which there are many) and instead target the pathophysiology underlying MECP2 disorders. Further work could bring antisense oligonucleotides, deep brain stimulation, and gene therapy into the clinic within the next decade or so.
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