Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment.

Recent proteome and transcriptome profiling of Alzheimer's disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, erroneous splicing events, neuronal degeneration and cognitive impairment.

Age-dependent expression pattern in the mammalian brain of a novel, small peptide encoded in the 22q11.2 deletion syndrome region.

22q11.2 deletion syndrome (22q11.2DS) carries increased risk for both physical and psychiatric symptoms, including a high risk for schizophrenia.

SCYL2 Protects CA3 Pyramidal Neurons from Excitotoxicity during Functional Maturation of the Mouse Hippocampus.

Neuronal death caused by excessive excitatory signaling, excitotoxicity, plays a central role in neurodegenerative disorders. The mechanisms regulating this process, however, are still incompletely understood. Here we show that the coated vesicle-associated kinase SCYL2/CVAK104 plays a critical role for the normal functioning of the nervous system and for suppressing excitotoxicity in the developing hippocampus.

Non-coding RNA regulation of synaptic plasticity and memory: implications for aging.

Advancing age is associated with the loss of cognitive ability and vulnerability to debilitating mental diseases. Although much is known about the development of cognitive processes in the brain, the study of the molecular mechanisms governing memory decline with aging is still in its infancy. Recently, it has become apparent that most of the human genome is transcribed into non-coding RNAs (ncRNAs) rather than protein-coding mRNAs.

A Synaptic Function Approach to Investigating Complex Psychiatric Diseases.

The 22q11 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans and presents with a complex and variable psychiatric phenotype. Patients show cognitive impairment and have a higher probability of psychiatric disorders. As much as 30% of patients with 22q11DS suffer from schizophrenia, the strongest association between any mutation and the disease.

Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia.

The 22q11 deletion syndrome (22q11DS) is characterized by multiple physical and psychiatric abnormalities and is caused by the hemizygous deletion of a 1.5-3 Mb region of chromosome 22. It constitutes one of the strongest known genetic risks for schizophrenia; schizophrenia arises in as many as 30% of patients with 22q11DS during adolescence or early adulthood.

Homologs of genes expressed in Caenorhabditis elegans GABAergic neurons are also found in the developing mouse forebrain.

Background: In an effort to identify genes that specify the mammalian forebrain, we used a comparative approach to identify mouse homologs of transcription factors expressed in developing Caenorhabditis elegans GABAergic neurons. A cell-specific microarray profiling study revealed a set of transcription factors that are highly expressed in embryonic C. elegans GABAergic neurons.

Dysregulation of presynaptic calcium and synaptic plasticity in a mouse model of 22q11 deletion syndrome.

The 22q11 deletion syndrome (22q11DS) is characterized by cognitive decline and increased risk of psychiatric disorders, mainly schizophrenia. The molecular mechanisms of neuronal dysfunction in cognitive symptoms of 22q11DS are poorly understood. Here, we report that a mouse model of 22q11DS, the Df(16)1/+ mouse, exhibits substantially enhanced short- and long-term synaptic plasticity at hippocampal CA3-CA1 synapses, which coincides with deficits in hippocampus-dependent spatial memory.

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration.

Mitochondria are key regulators of cell viability and provide essential functions that protect against neurodegenerative disease. To develop a model for mitochondrial-dependent neurodegeneration in Caenorhabditis elegans, we used RNA interference (RNAi) and genetic ablation to knock down expression of enzymes in the Coenzyme Q (CoQ) biosynthetic pathway. CoQ is a required component of the ATP-producing electron transport chain in mitochondria.

RGS9-2 modulates D2 dopamine receptor-mediated Ca2+ channel inhibition in rat striatal cholinergic interneurons.

Regulator of G protein signaling (RGS) proteins negatively regulate receptor-mediated second messenger responses by enhancing the GTPase activity of Galpha subunits. We describe a receptor-specific role for an RGS protein at the level of an individual brain neuron. RGS9-2 and Gbeta(5) mRNA and protein complexes were detected in striatal cholinergic and gamma-aminobutyric acidergic neurons.