IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

Elevated Proteasome Capacity Extends Replicative Lifespan in Saccharomyces cerevisiae

Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS–related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Molecular karyotyping in 17 patients and mutation screening in 41 patients with Kabuki syndrome.

The Kabuki syndrome (KS, OMIM 147920), also known as the Niikawa-Kuroki syndrome, is a multiple congenital anomaly/mental retardation syndrome characterized by a distinct facial appearance. The cause of KS has been unidentified, even by whole-genome scan with array comparative genomic hybridization (CGH). In recent years, high-resolution oligonucleotide array technologies have enabled us to detect fine copy number alterations. In 17 patients with KS, molecular karyotyping was carried out with GeneChip 250K NspI array (Affymetrix) and Copy Number Analyser for GeneChip (CNAG). It showed seven copy number alterations, three deleted regions and four duplicated regions among the patients, with the exception of registered copy number variants (CNVs). Among the seven loci, only the region of 9q21.11-q21.12 ( approximately 1.27 Mb) involved coding genes, namely, transient receptor potential cation channel, subfamily M, member 3 (TRPM3), Kruppel-like factor 9 (KLF9), structural maintenance of chromosomes protein 5 (SMC5) and MAM domain containing 2 (MAMDC2). Mutation screening for the genes detected 10 base substitutions consisting of seven single-nucleotide polymorphisms (SNPs) and three silent mutations in 41 patients with KS. Our study could not show the causative genes for KS, but the locus of 9q21.11-q21.12, in association with a cleft palate, may contribute to the manifestation of KS in the patient. As various platforms on oligonucleotide arrays have been developed, higher resolution platforms will need to be applied to search tiny genomic rearrangements in patients with KS.Journal of Human Genetics (2009) 54, 304-309; doi:10.1038/jhg.2009.30; published online 03 April 2009