Impas 1 possesses endoproteolytic activity against multipass membrane protein substrate cleaving the presenilin 1 holoprotein

AbstractPresenilins (PS1 and PS2) are supposed to be unusual aspartic proteases and components of the γ-secretase complex regulating cleavage of type I proteins. Multiple mutations in PS1 are a major cause of familial early-onset Alzheimer’s disease (AD). We and others recently identified PS-related families of proteins (IMPAS/PSH/signal peptide peptidases (SPP)). The functions of these proteins are yet to be determined. We found that intramembrane protease-associated or intramembrane protease aspartic protein Impas 1 (IMP1)/SPP induces intramembranous cleavage of PS1 holoprotein in cultured cells coexpressing these proteins. Mutations in evolutionary invariant sites in hIMP1 or specific γ-secretase inhibitors abolish the hIMP1-mediated endoproteolysis of PS1. In contrast, neither AD-like mutations in hIMP1 nor in PS1 substrate abridge the PS1 cleavage. The data suggest that IMP1 is a bi-aspartic polytopic protease capable of cleaving transmembrane precursor proteins. These data, to our knowledge, are a first observation that a multipass transmembrane protein or the integral protease per se may be a primary substrate for an intramembranous proteolysis

Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer\u27s disease

The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/PS2) underlie production of beta-amyloid, the key process in Alzheimer\u27s disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the gamma-cleavage activities of PSENs that produce Abeta, but not the epsilon-like cleavage activity that release physiologically essential transcription activators, is a potential approach for the development of rational therapies for AD. In order to identify whether different activities of PSEN1 can be dissociated, we designed multiple mutations in the evolutionary conserved sites of PSEN1. We tested them in vitro and in vivo assays and compared their activities with mutant isoforms of presenilin-related intramembrane di-aspartyl protease (IMPAS1 (IMP1)/signal peptide peptidase (SPP)). PSEN1 auto-cleavage was more resistant to the mutation remodeling than the epsilon-like proteolysis. PSEN1 with a G382A or a P433A mutation in evolutionary invariant sites retains functionally important APP epsilon- and Notch S3- cleavage activities, but G382A inhibits APP gamma-cleavage and Abeta production and a P433A elevates Abeta. The G382A variant cannot restore the normal cellular ER Ca(2+) leak in PSEN1/PSEN2 double knockout cells, but efficiently rescues the loss-of-function (Egl) phenotype of presenilin in C. elegans. We found that, unlike in PSEN1 knockout cells, endoplasmic reticulum (ER) Ca(2+) leak is not changed in the absence of IMP1/SPP. IMP1/SPP with the analogous mutations retained efficiency in cleavage of transmembrane substrates and rescued the lethality of Ce-imp-2 knockouts. In summary, our data show that mutations near the active catalytic sites of intramembrane di-aspartyl proteases have different consequences on proteolytic and signaling functions

Complete Mitochondrial Genome and Phylogeny of Pleistocene MammothMammuthus primigenius

Phylogenetic relationships between the extinct woolly mammoth(Mammuthus primigenius), and the Asian(Elephas maximus) and African savanna(Loxodonta africana) elephants remain unresolved. Here, we report the sequence of the complete mitochondrial genome (16,842 base pairs) of a woolly mammoth extracted from permafrost-preserved remains from the Pleistocene epoch—the oldest mitochondrial genome sequence determined to date. We demonstrate that well-preserved mitochondrial genome fragments, as long as ~1,600–1700 base pairs, can be retrieved from pre-Holocene remains of an extinct species. Phylogenetic reconstruction of the Elephantinae clade suggests thatM. primigenius andE. maximus are sister species that diverged soon after their common ancestor split from theL. africana lineage. Low nucleotide diversity found between independently determined mitochondrial genomic sequences of woolly mammoths separated geographically and in time suggests that north-eastern Siberia was occupied by a relatively homogeneous population ofM. primigenius throughout the late Pleistocene

PS1 Alzheimer's disease family with spastic paraplegia: the search for a gene modifier

PS1 mutations are associated with classic Alzheimer's disease (AD); however, some families develop AD and spastic paraplegia (SP) with brain pathology characterized by Abeta cotton wool plaques. The authors report a variant AD family with the E280Q PS1 mutation. The fact that the same PS1 mutation can be found in patients with either variant or classic AD argues in favor of the presence of a genetic modifier. The authors have excluded that this modifier effect originates from coding sequence variations in three SP genes or from a second mutation in the other AD genes

A novel PS1 case of variant Alzheimer’s Disease with Spastic Paraplegia: the search for a gene-modifier

Abstract no. 118

PS1 Alzheimer's disease family with spastic paraplegia: The search for a gene modifier

PS1 mutations are associated with classic Alzheimer's disease (AD); however, some families develop AD and spastic paraplegia (SP) with brain pathology characterized by Aβ cotton wool plaques. The authors report a variant AD family with the E280Q PS1 mutation. The fact that the same PS1 mutation can be found in patients with either variant or classic AD argues in favor of the presence of a genetic modifier. The authors have excluded that this modifier effect originates from coding sequence variations in three SP genes or from a second mutation in the other AD genes.link_to_subscribed_fulltex

Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH

The molecular mechanisms controlling human hair growth and scalp hair loss are poorly understood. By screening about 350,000 individuals in two populations from the Volga-Ural region of Russia, we identified a gene mutation in families who show an inherited form of hair loss and a hair growth defect. Affected individuals were homozygous for a deletion in the LIPH gene on chromosome 3q27, caused by short interspersed nuclear element-retrotransposon-mediated recombination. The LIPH gene is expressed in hair follicles and encodes a phospholipase called lipase H (alternatively known as membrane-associated phosphatidic acid-selective phospholipase A1alpha), an enzyme that regulates the production of bioactive lipids. These results suggest that lipase H participates in hair growth and development

Chromosome 10 and 12 loci for late-onset Alzheimer’s Disease: genetic linkage and case-control association studies

Abstract no. 116

Paenungulata Tree and Phylogenic Relationship of the Woolly Mammoth

<p>The analysis of complete mtDNA sequences placesM. primigenius withE. maximus on the tree. The Sirenia<i>(D. dugon)</i> and Hyracoidea<i>(P. capensis),</i> most closely related species among extant taxa to Elephantinae, were taken as outgroups. Bootstrap values and posterior probabilities were calculated using a Bayesian approach [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040073#pbio-0040073-b029" target="_blank">29</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040073#pbio-0040073-b031" target="_blank">31</a>] assuming a gamma distribution of the rates of evolution across sites with a General Time Reversible model (normal font), HKY model (bold), with a parsimony approach (italic), and by neighbor joining (italic and bold) [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040073#pbio-0040073-b028" target="_blank">28</a>]. The scale is 0.1 substitutions per site. The mitochondrial genomes of<i>M. primigenius, E. maximus A, E. maximus B, L. africana A, L. africana B, D. dugon,</i> andP. capensis were used in the analysis.</p

The Right Back Leg of the Woolly Mammoth<i>(M. primigenius)</i> Found in Siberia

<p>The well-preserved mammoth body fragment with foot (33 × 36 cm), shin, and ankle-joint (the total length is ~88 cm) was found in the Enmynveem River valley (north-eastern Siberia, Chukotka). The tissue material (bones, muscles, and skin) had no visible marks of tissue damage by insects or other animals. Radiocarbon dating of the skin and muscle tissue determined that the mammoth lived 32,850 ± 900 y ago [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040073#pbio-0040073-b012" target="_blank">12</a>].</p