siRNA-based identification of IBD-related targets in human monocyte-derived dendritic cells.

Inflammatory bowel disease (IBD) is thought to be caused by an aberrant host response to the commensal enteric flora in genetically susceptible individuals. Dendritic cells (DCs) play a key role in the regulation of this response as they sample gut commensals. In healthy individuals DCs actively contribute to tolerance upon recognition of these resident bacteria, whereas in individuals with IBD, DCs will initiate an inflammatory response.

Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington's disease.

Age-related neurodegenerative disorders including Alzheimer's disease and Huntington's disease (HD) consistently show elevated DNA damage, but the relevant molecular pathways in disease pathogenesis remain unclear. One attractive gene is that encoding the ataxia-telangiectasia mutated (ATM) protein, a kinase involved in the DNA damage response, apoptosis, and cellular homeostasis. Loss-of-function mutations in both alleles of ATM cause ataxia-telangiectasia in children, but heterozygous mutation carriers are disease-free.

Modest proteasomal inhibition by aberrant ubiquitin exacerbates aggregate formation in a Huntington disease mouse model.

UBB(+1), a mutant form of ubiquitin, is both a substrate and an inhibitor of the proteasome which accumulates in the neuropathological hallmarks of Huntington disease (HD). In vitro, expression of UBB(+1) and mutant huntingtin synergistically increase aggregate formation and polyglutamine induced cell death. We generated a UBB(+1) transgenic mouse line expressing UBB(+1) within the neurons of the striatum.

Ubiquitin-conjugating enzyme E2-25K increases aggregate formation and cell death in polyglutamine diseases.

Polyglutamine diseases are characterized by neuronal intranuclear inclusions of expanded polyglutamine proteins, which are also ubiquitinated, indicating impairment of the ubiquitin-proteasome system. E2-25K (Hip2), an ubiquitin-conjugating enzyme, interacts directly with huntingtin and may mediate ubiquitination of the neuronal intranuclear inclusions in Huntington disease. E2-25K could thus modulate aggregation and toxicity of expanded huntingtin.

Conformational diseases: an umbrella for various neurological disorders with an impaired ubiquitin-proteasome system.

It is increasingly appreciated that failures in the ubiquitin-proteasome system play a pivotal role in the neuropathogenesis of many neurological disorders. This system, involved in protein quality control, should degrade misfolded proteins, but apparently during neuropathogenesis, it is unable to cope with a number of proteins that, by themselves, can consequently accumulate. Ubiquitin is essential for ATP-dependent protein degradation by the proteasome.

Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases.

Polyglutamine diseases are characterized by neuronal intranuclear inclusions (NIIs) of expanded polyglutamine proteins, indicating the failure of protein degradation. UBB(+1), an aberrant form of ubiquitin, is a substrate and inhibitor of the proteasome, and was previously reported to accumulate in Alzheimer disease and other tauopathies. Here, we show accumulation of UBB(+1) in the NIIs and the cytoplasm of neurons in Huntington disease and spinocerebellar ataxia type-3, indicating inhibition of the proteasome by polyglutamine proteins in human brain.

Repair of UV lesions in silenced chromatin provides in vivo evidence for a compact chromatin structure.

Genes positioned close to telomeres in yeast are silenced by a heterochromatin-like structure containing Sir proteins. To investigate whether silencing also affects DNA repair, we studied removal of UV lesions by photolyase and nucleotide excision repair (NER) in strains containing the URA3 gene inserted 2 kilobases from a telomere. URA3 was transcriptionally active in sir3delta mutants, partially silenced in SIR3 cells, or completely silenced by overexpression of SIR3 or deletion of RPD3.