Localization of a novel type trypsin‐like serine protease, neurosin, in brain tissues of Alzheimer's disease and Parkinson's disease

Ogawa, Kenichi; Yamada, Tatsuo; Tsujioka, Y.; Taguchi, Junichi; Takahashi, Mitsuo; Tsuboi, Yoshio; Fujino, Yasuhiro; Nakajima, Masashi; Yamamoto, Takashi; Akatsu, Hiroyasu; Mitsui, Sinichi; Yamaguchi, Naohito

doi:10.1046/j.1440-1819.2000.00731.x

Cited by 92 publications

(82 citation statements)

References 22 publications

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“…Furthermore, Little et al (1997) detected positive hK6 immunostaining in monkey cortex cells lining the perimeter of cortical microvessels, in brains of human patients with Alzheimer's disease, and in microglial cells, indicating a role of this protease in brain disease. Furthermore, new knowledge about human kallikrein 6 suggests a role in neurodegenerative diseases (Diamandis et al 2000c;Ogawa et al 2000;Okui et al 2001;Bernett et al 2002;Blaber et al 2002;Gomis-Ruth et al 2002). It will be useful to examine the involvement of hK13 and other kallikreins in human neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Human Kallikrein 13 Expression in Normal Tissues: An Immunohistochemical Study

Petraki

Karavana

Diamandis

2003

J Histochem Cytochem.

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S U M M A R YThe human tissue kallikrein 13 gene (KLK13), encoding for hK13 protein, was recently cloned and characterized. Here we describe the immunohistochemical (IHC) localization of hK13 in normal human tissues and compare it with the expression of two other kallikreins, hK6 and hK10. We performed the streptavidin-biotin IHC method on 204 paraffin blocks from archival, current, and autopsy material prepared from almost every normal human tissue, using a polyclonal and a monoclonal hK13 antibody. The staining was cytoplasmic and both antibodies yielded similar results. The hK13 protein was revealed in a variety of tissues, mainly in glandular epithelia. Other epithelia that expressed hK13 included the urothelium, the spermatic epithelium, and the epithelium of the choroid plexus. hK13 was intensely immunoexpressed by some endocrine organs, such as the adenohypophysis, the thyroid gland, the parathyroid glands, the adrenal medulla, the Leydig cells of the testis, and the cells of the endocrine pancreas. Immunoreactivity was also observed in the primordial follicles, the corpus luteum, and sparse luteinized cells in the stroma of the ovary, the trophoblastic cells of the placenta, the Hassall's corpuscles of the thymus, and chondrocytes. Nerves and ganglia of the peripheral nervous system, and both neurons and glial cells in the central nervous system, were positive. In short, hK13 was expressed by many glandular epithelia, some endocrine organs, and some specialized epithelia and cells. Comparison of these data with hK6 and hK10 expression suggests that the three kallikreins have a similar IHC pattern in normal human tissues.

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Section: Discussionmentioning

confidence: 99%

Human Kallikrein 13 Expression in Normal Tissues: An Immunohistochemical Study

Petraki

Karavana

Diamandis

2003

J Histochem Cytochem.

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“…Like the other members of the human kallikrein family, the KLK6 gene lies at chromosome locus 19q13.4, telomeric to the PSA (KLK3) and KLK2 genes (5,21). (Pro)hK6 or its mRNA was found in human brain, spinal cord, cerebellum, kidney, uterus, mammary gland, pancreatic tissue, cerebrospinal fluid, prostate and salivary glands and, at a lower level, in spleen (16,27,28,33,34). Immunohistochemical localization of hK6 in various tissues, showing epithelial cell secretion, has been published (35).…”

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confidence: 99%

“…It is decreased in Parkinson's disease and Alzheimer's disease patients (33). Cells transfected with the enzyme and amyloid precursor protein accumulate amyloidogenic fragments (28).…”

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confidence: 99%

The Structure of Human Prokallikrein 6 Reveals a Novel Activation Mechanism for the Kallikrein Family

Gomis‐Rüth¹,

Bayés²,

Sotiropoulou³

et al. 2002

Journal of Biological Chemistry

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Zyme/protease M/neurosin/human kallikrein 6 (hK6) is a member of the human kallikrein family of trypsinlike serine proteinases and was originally identified as being down-regulated in metastatic breast and ovarian tumors when compared with corresponding primary tumors. Recent evidence suggests that hK6 may serve as a circulating tumor marker in ovarian cancers. In addition, it was described in the brain of Parkinson's disease and Alzheimer's disease patients, where it is implicated in amyloid precursor protein processing. It is thus a biomarker for these diseases. To examine the mechanism of activation of hK6, we have solved the structure of its proform, the first of a human kallikrein family member. The proenzyme displays a fold that exhibits chimeric features between those of trypsinogen and other family members. It lacks the characteristic "kallikrein loop" and forms the six disulfide bridges of trypsin. Pro-hK6 displays a completely closed specificity pocket and a unique conformation of the regions involved in structural rearrangements upon proteolytic cleavage activation. This points to a novel activation mechanism, which could be extrapolated to other human kallikreins.

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“…Besides these genes, however, four other genes included in these CNVs encode proteins whose function is firmly related to the Ab biological network: KLK6 (19q13.33) encodes neurosin, a secreted kallikrein-like protease localised in senile plaques and neurofibrillary tangles of AD brains. 11 Cells cotransfected with APP and KLK6 release an abundance of amyloidergic N-truncated Ab peptides and concomitantly, show a reduction of production of non-amyloidergic species resulting from alpha secretase activity. 12 MEOX2 (7p21.1) encodes a homeobox protein, known to be a regulator of vascular differentiation, whose expression is low in AD.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease

Rovelet‐Lecrux¹,

Legallic²,

Wallon³

et al. 2011

Eur J Hum Genet

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Investigators of the GMAJ project 12Studying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-b peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Ab metabolism or signalling, and for which animal or cellular models have already been developed. European Journal of Human Genetics (2012) 20, 613-617; doi:10.1038/ejhg.2011; published online 14 December 2011Keywords: Alzheimer disease; copy number variations; KLK6; MEOX2; SLC30A3; FPR2 INTRODUCTIONThe identification of major genes (PSEN1, PSEN2 and APP) responsible for autosomal dominant early-onset Alzheimer disease (ADEOAD, OMIM number #104300) has proved crucial to understanding the pathophysiology of the disease. It has allowed for the definition of the amyloid cascade hypothesis, 1,2 according to which accumulation of highly aggregable forms of the amyloid beta (Ab) peptide, that results from the amyloid precursor protein (APP) proteolytic cleavage, is the primum movens of this devastating neurodegenerative disease. ADEOAD is a rare condition with a prevalence rate estimated at 5.3 per 100 000 persons at risk. 2 Mutation screening of more than 150 ADEOAD families, ascertained in France by the National Centre for early-onset AD (CNR-MAJ), had shown that mutations of known genes account for 85% of ADEOAD families. 3 We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes. Indeed, a previous analysis has shown that APP locus duplications were present in a subset of these families. 4 To further explore this issue, we conducted a genome-wide screen for CNVs, using high-resolution oligonucleotide array-based comparative genomic hybridisation (a-CGH) in still unexplained ADEOAD families. In addition, as rare pathogenic CNVs often occur de novo, 5 we decided to investigate by a-CGH another subgroup of patients consisting of 12 sporadic cases with particularly young disease onset...

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Localization of a novel type trypsin‐like serine protease, neurosin, in brain tissues of Alzheimer's disease and Parkinson's disease

Cited by 92 publications

References 22 publications

Human Kallikrein 13 Expression in Normal Tissues: An Immunohistochemical Study

Human Kallikrein 13 Expression in Normal Tissues: An Immunohistochemical Study

The Structure of Human Prokallikrein 6 Reveals a Novel Activation Mechanism for the Kallikrein Family

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease

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