Alzheimer Research Forum Discussion: Gain or Loss of Function – Time to Shake up Assumptions on γ-Secretase in Alzheimer Disease?

The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of SorLA protein. An initial screening, based on the overexpression of 71 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variations (R332W, S577P, and R654W) and two maturation-competent variations (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs were associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Finally, structural analysis of the impact of missense variations on SorLA protein structure indicated that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein structure resulting from changes in the interatomic interactions.

Download Full-text

Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

10.1101/541730 ◽

2019 ◽

Author(s):

Mercedes M. Pérez-Jiménez ◽

Paula Sansigre ◽

Amador Valladares ◽

Mónica Venegas-Calerón ◽

Alicia Sánchez-García ◽

...

Keyword(s):

Alzheimer Disease ◽

Drug Treatment ◽

Steroid Hormones ◽

Sensory Neurons ◽

Environmental Cues ◽

Steroid Sulfatase ◽

Loss Of Function ◽

C Elegans ◽

Age Related ◽

Signalling Process

Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity by a still not fully understood mechanism. We find that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones and increases longevity. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) and is not additive to the longevity of germline-less mutants. Noteworthy, sul-2 mutations do not affect fertility. Thus, STS inactivation affects the germline signalling process regulating longevity. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of germline longevity by environmental cues. We also demonstrate that treatment with the specific STS inhibitor STX64, reproduces the longevity phenotype of sul-2 mutants. Remarkably, STS inhibition by either mutation or drug treatment ameliorates protein aggregation diseases in C. elegans models of Parkinson, Huntington and Alzheimer, as well as Alzheimer disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors for the treatment of aging and aging related diseases.

Download Full-text

Loss-of-Function PCSK9 Mutations Are Not Associated With Alzheimer Disease

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/0891988718764330 ◽

2018 ◽

Vol 31 (2) ◽

pp. 90-96 ◽

Cited By ~ 6

Author(s):

Martine Paquette ◽

Yascara Grisel Luna Saavedra ◽

Judes Poirier ◽

Louise Théroux ◽

Doris Dea ◽

...

Keyword(s):

Alzheimer Disease ◽

Age Of Onset ◽

Late Onset ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Founder Population ◽

Loss Of Function ◽

Low Density Lipoprotein Cholesterol ◽

Pcsk9 Inhibitors ◽

Neutral Effect

Background: Hypercholesterolemia is a major risk factor for the late-onset form of Alzheimer disease (AD). Loss-of-function (LOF) mutations of PCSK9 and PCSK9 inhibitors lower low-density lipoprotein cholesterol (LDL-C) and have been associated with a reduced risk of cardiovascular disease. The aim of this study was to examine the effect of PCSK9 LOF variants on risk and age of onset of AD. Methods: A total of 878 participants (410 controls and 468 AD cases) from the Quebec Founder Population were included in the study. Results: Fifty-four (6.2%) participants carried the R46L mutation, whereas 226 (26.2%) participants carried the InsLEU mutation. There was no protective or no deleterious effect of carrying PCSK9 LOF mutations on AD prevalence nor on age of onset, even when stratified by apolipoprotein E epsilon 4 genotype or by gender. Conclusion: Our data indicate that carrying PCSK9 LOF mutations has a neutral effect on neurocognitive health and the prevalence of AD.

Download Full-text

Clinical characteristics of loss-of-function mutations in ABCA7 in Belgian Alzheimer disease patients and families

Frontiers in Neuroscience ◽

10.3389/conf.fnins.2015.89.00077 ◽

2015 ◽

Vol 9 ◽

Author(s):

Van Den Bossche Tobi ◽

Sleegers Kristel ◽

Cuyvers Elise ◽

Engelborghs Sebastiaan ◽

Vandenbulcke Mathieu ◽

...

Keyword(s):

Alzheimer Disease ◽

Clinical Characteristics ◽

Loss Of Function

Download Full-text

A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease

Molecular Psychiatry ◽

10.1038/s41380-018-0091-8 ◽

2018 ◽

Vol 25 (3) ◽

pp. 629-639 ◽

Cited By ~ 15

Author(s):

Daniela Hartl ◽

◽

Patrick May ◽

Wei Gu ◽

Manuel Mayhaus ◽

...

Keyword(s):

Alzheimer Disease ◽

Late Onset ◽

Loss Of Function ◽

Familial Alzheimer Disease

Download Full-text

ABCA7 loss-of-function variants, expression, and neurologic disease risk

Neurology Genetics ◽

10.1212/nxg.0000000000000126 ◽

2017 ◽

Vol 3 (1) ◽

pp. e126 ◽

Cited By ~ 16

Author(s):

Mariet Allen ◽

Sarah J. Lincoln ◽

Morgane Corda ◽

Jens O. Watzlawik ◽

Minerva M. Carrasquillo ◽

...

Keyword(s):

Alzheimer Disease ◽

Messenger Rna ◽

Disease Risk ◽

Late Onset ◽

Common Mechanism ◽

Mrna Levels ◽

Loss Of Function ◽

Neurologic Diseases ◽

Lower Protein ◽

Coding Variants

Objective:To investigate and characterize putative “loss-of-function” (LOF) adenosine triphosphate–binding cassette, subfamily A member 7 (ABCA7) mutations reported to associate with Alzheimer disease (AD) risk.Methods:We genotyped 6 previously reported ABCA7 putative LOF variants in 1,465 participants with AD, 381 participants with other neuropathologies (non-AD), and 1,043 controls and assessed the overall mutational burden for association with different diagnosis groups. We measured brain ABCA7 protein and messenger RNA (mRNA) levels using Western blot and quantitative PCR, respectively, in 11 carriers of the 3 most common variants, and sequenced all 47 ABCA7 exons in these participants to screen for other coding variants.Results:At least one of the investigated variants was identified in 45 participants with late-onset Alzheimer disease, 12 participants with other neuropathologies, and 11 elderly controls. Association analysis revealed a significantly higher burden of these variants in participants with AD (p = 5.00E-04) and those with other neuropathologies (p = 8.60E-03) when compared with controls. Concurrent analysis of brain ABCA7 mRNA and protein revealed lower protein but not mRNA in p.L1403fs carriers, lower mRNA but not protein in p.E709fs carriers, and additional deleterious mutations in some c.5570+5G>C carriers.Conclusions:Our results suggest that LOF may not be a common mechanism for these ABCA7 variants and expand the list of neurologic diseases enriched for them.

Download Full-text

Compensatory Shift of Subcallosal Area and Paraterminal Gyrus White Matter Parameters on DTI in Patients with Alzheimer Disease

Current Alzheimer Research ◽

10.2174/1567205015666171227155510 ◽

2018 ◽

Vol 15 (6) ◽

pp. 590-599 ◽

Cited By ~ 3

Author(s):

Barbora Kuchtova ◽

Zdenek Wurst ◽

Jana Mrzilkova ◽

Ibrahim Ibrahim ◽

Jaroslav Tintera ◽

...

Keyword(s):

White Matter ◽

Alzheimer Disease ◽

Diffusion Tensor ◽

Hippocampal Formation ◽

Memory Function ◽

Disease Diagnosis ◽

Compensatory Hypertrophy ◽

Control Group ◽

Loss Of Function ◽

Subsequent Loss

Objective: Alzheimer disease is traditionally conceptualized as a disease of brain gray matter, however, studies with diffusion tensor imaging have demonstrated that Alzheimer disease also involves alterations in white matter integrity. We measured number of tracts, tracts length, tract volume, quantitative anisotropy and general fractional anisotropy of neuronal tracts in subcallosal area, paraterminal gyrus and fornix in patients with Alzheimer disease and healthy age-matched controls. Our hypothesis was that patients with Alzheimer disease should exhibit decrease in the integrity of these white matter structures that are crucial for semantic memory function. Methods: For our study were selected 24 patients with confirmed Alzheimer disease diagnosis and 24 healthy controls (AD center, Department of Neurology, Charles University, Prague, Czech Republic). Statistically significant differences between the patients with Alzheimer disease and the control group were found both on the left and right fornices but only concerning the tract numbers and tract length. The subcallosal area and paraterminal gyrus showed statistically significant differences between the patients with Alzheimer disease and the control group, but only on the left side and only associated with the tract volume and quantitative anisotropy. Conclusion: Our explanation for these findings lies in the severe hippocampal atrophy (and subsequent loss of function) with compensatory hypertrophy of the subcallosal area and paraterminal gyrus neuronal fibers that occurs in Alzheimer's disease, as an adaptation to the loss of projection from the hippocampal formation via fornix.

Download Full-text

DPP6 gene in European American Alzheimer’s Disease

10.1101/2020.10.23.20216408 ◽

2020 ◽

Author(s):

Laxmi Kirola ◽

John P. Budde ◽

Fengxian Wang ◽

Joanne Norton ◽

John C. Morris ◽

...

Keyword(s):

Alzheimer Disease ◽

Early Onset ◽

Late Onset ◽

Transmembrane Protein ◽

Loss Of Function ◽

Sequencing Project ◽

Or Gene ◽

The Brain ◽

Significant Statistical Association ◽

Hispanic White

AbstractDPP6 encodes a transmembrane protein that expresses highly in the hippocampal regions of the brain and regulates dendritic excitability. Recently, rare and loss of function variants were reported in DPP6 and further demonstrated to be associated with early onset Alzheimer Disease (AD) and frontotemporal dementia. We performed single variant and gene-based analyses in three non-Hispanic white cohorts: a familial late onset AD (cases=1212, controls=341), an unrelated early onset AD (cases=1385, controls=3864) and in the unrelated Alzheimer disease sequencing project (ADSP, cases=5679, controls=4601). Neither single variant or gene-based analysis revealed any significant statistical association of DPP6 variants with the risk for AD in the cohorts examined.

Download Full-text

Evolutionary history of Alzheimer Disease causing protein family Presenilins with pathological implications

10.1101/394270 ◽

2018 ◽

Author(s):

Ammad Aslam Khan ◽

Bushra Mirza ◽

Hashim Ali Raja

Keyword(s):

Alzheimer Disease ◽

Protein Trafficking ◽

Developmental Disorders ◽

Purifying Selection ◽

Beta Catenin ◽

Gamma Secretase ◽

Loss Of Function ◽

Last Common Eukaryotic Ancestor ◽

History Of ◽

Almost All

AbstractPresenilin proteins are type II transmembrane proteins. They make the catalytic component of Gamma secretase, a multiportion transmembrane protease. Amyloid protein, Notch and beta catenin are among more than 90 substrates of Presenilins. Mutations in Presenilins lead to defects in proteolytic cleavage of its substrate resulting in some of the most devastating pathological conditions including Alzheimer disease (AD), developmental disorders and cancer. In addition to catalytic roles, Presenilin protein is also shown to be involved in many non-catalytic roles i.e. calcium homeostasis, regulation of autophagy and protein trafficking etc. These proteolytic proteins are highly conserved, present in almost all the major eukaryotic groups. Studies on wide variety of organisms ranging from human to unicellular dictyostelium have shown the important catalytic and non-catalytic roles of Presenilins. In the current research project, we aimed to elucidate the phylogenetic history of Presenilins. We showed that Presenilins are the most ancient of the Gamma secretase proteins and might have their origin in last common eukaryotic ancestor (LCEA). We also demonstrated that these proteins have been evolving under strong purifying selection. Through evolutionary trace analysis, we showed that Presenilin protein sites which undergoes mutations in Familial Alzheimer Disease are highly conserved in metazoans. Finally, we discussed the evolutionary, physiological and pathological implication of our findings and proposed that evolutionary profile of Presenilins supports the loss of function hypothesis of AD pathogenesis.

Download Full-text