Polymorphisms in neprilysin gene affect the risk of Alzheimer's disease in Finnish patients

Helisalmi, Seppo; Hiltunen, Mikko; Vepsäläinen, Saila; Iivonen, Susan; Mannermaa, Arto; Lehtovirta, Maarit; Koivisto, AM; Alafuzoff, Irina; Soininen, Hilkka

doi:10.1136/jnnp.2004.036574

Cited by 57 publications

(49 citation statements)

References 13 publications

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“…11 Population genetic studies suggest that polymorphisms in the neprilysin gene are associated with altered risk of lateonset AD. 16,17 Together, these studies suggest that neprilysin plays a vital physiological role in Ab clearance and support the hypothesis that elevating neprilysin activity in brains containing high Ab levels is likely to lower Ab levels and may ameliorate AD pathology and symptoms.…”

Section: Introductionsupporting

confidence: 63%

Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo

et al. 2006

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Section: Introductionsupporting

confidence: 63%

Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo

et al. 2006

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“…Here, we identified not only APP but also its regulators such as membrane metalloendopeptidase (Mme) and protein phosphatase 3, catalytic subunit, ␣ isoform (Ppp3ca). Mme has a role in the degradation of excess and misfolded APP peptide (64), and the activity of protein phosphatase tightly regulates APP secretion (65). In addition, we found six proteins that are related to diabetes, a disease characterized by insulin resistance and hyperinsulinemia.…”

Section: Distribution Of Glyco-and Phosphopeptides In Erlic-mentioning

confidence: 86%

Simultaneous Characterization of Glyco- and Phosphoproteomes of Mouse Brain Membrane Proteome with Electrostatic Repulsion Hydrophilic Interaction Chromatography

Zhang

Guo

et al. 2010

Molecular & Cellular Proteomics

101

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Characterization of glyco-and phosphoproteins as well as their modification sites poses many challenges, the greatest being loss of their signals during mass spectrometric detection due to substoichiometric amounts and the ion suppression effect caused by peptides of high abundance. We report here an optimized protocol using electrostatic repulsion hydrophilic interaction chromatography for the simultaneous enrichment of glyco-and phosphopeptides from mouse brain membrane protein digest. With this protocol, we successfully identified 544 unique glycoproteins and 922 glycosylation sites, which were significantly higher than those from the commonly used hydrazide chemistry method (192 glycoproteins and 345 glycosylation sites). Moreover, a total of 383 phosphoproteins and 915 phosphorylation sites were recovered from the sample, suggesting that this protocol has the potential to enrich both glycopeptides and phosphopeptides simultaneously. Of the total 995 glycosylation sites identified from both methods, 96% were considered new as they were either annotated as putative or not documented in the newly released Swiss-Prot database. Thus, this study could be of significant value in complementing the current glycoprotein database and provides a unique opportunity to study the complex interaction of two different post-translational modifications in health and disease without being affected by interexperimental variations. Molecular & Cellular Proteomics 9:635-647, 2010.

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“…In contrast, Thomas et al showed that the learning abilities were not reduced in older NEP knockout mice; rather, they were significantly improved, and Aβ deposits could not be detected by immunohistochemical methods, in spite of the elevated Aβ levels in the brains of these mice 46. In humans, no mutation in the MME gene linked to familial Alzheimer's disease has been reported, although some nucleotide repeat polymorphisms have been reported to be associated with susceptibility to sporadic Alzheimer's disease 47, 48. We hypothesized that human NEP deficiency would lead to cognitive impairment and increased Aβ plaque accumulation.…”

Section: Discussionmentioning

confidence: 99%

Mutations in MME cause an autosomal‐recessive Charcot–Marie–Tooth disease type 2

Higuchi

Hashiguchi

Yuan

et al. 2016

Annals of Neurology

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ObjectiveThe objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT.MethodsTo efficiently identify novel causative genes for AR‐CMT, we analyzed 303 unrelated Japanese patients with CMT using whole‐exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation.ResultsWe identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta‐amyloid (Aβ)‐degrading enzymes. All patients had a similar phenotype consistent with late‐onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss‐of‐function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aβ in Pittsburgh compound‐B positron emission tomography imaging.InterpretationOur results indicate that loss‐of‐function MME mutations are the most frequent cause of adult‐onset AR‐CMT2 in Japan, and we propose that this new disease should be termed AR‐CMT2T. A loss‐of‐function MME mutation did not cause early‐onset Alzheimer's disease. Identifying the MME mutation responsible for AR‐CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT. Ann Neurol 2016;79:659–672

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Polymorphisms in neprilysin gene affect the risk of Alzheimer's disease in Finnish patients

Cited by 57 publications

References 13 publications

Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo

Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer's disease-related amyloid-β peptide in vivo

Simultaneous Characterization of Glyco- and Phosphoproteomes of Mouse Brain Membrane Proteome with Electrostatic Repulsion Hydrophilic Interaction Chromatography

Mutations in MME cause an autosomal‐recessive Charcot–Marie–Tooth disease type 2

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