Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes

Schwartzentruber, Jeremy; Cooper, Sarah; Liu, Yushi; Barrio-Hernandez, Iñigo; Bello, Erica; Kumasaka, Natsuhiko; Young, Adam M. H.; Franklin, R. J. M.; Johnson, Toby; Estrada, Karol; Gaffney, Daniel J; Beltrão, Pedro; Bassett, Andrew

doi:10.1038/s41588-020-00776-w

Cited by 328 publications

(371 citation statements)

References 112 publications

(134 reference statements)

Supporting

Mentioning

318

Contrasting

Order By: Relevance

“…Computational modeling and experimental analysis reveal that the substitution alters the receptor's interaction with the lipid bilayer, possibly restricting its lateral movement and favoring homo-interactions, receptor clustering and auto-activation. Constitutive activation of the EphA1 leads to aberrant downstream signaling of the small RhoGTPases, RhoA and Rac1, as previously demonstrated in several cellular and animal AD models [20][21][22][23][24][25][26][27][28][29][30].…”

Section: Introductionsupporting

confidence: 56%

Alzheimer’s disease-associated P460L mutation in ephrin receptor type A1 (EphA1) leads to dysregulated Rho-GTPase signaling

Kim

Lasso

Patel

et al. 2021

Preprint

View full text Add to dashboard Cite

Recently, late onset AD (LOAD) genome-wide association studies identified EphA1, a member of receptor tyrosine kinase family (RTK) as a disease associated loci. In the follow-up study where 3 independent LOAD cohorts were performed, a P460L coding mutation in EphA1 loci showed a significant association with LOAD. However, the role of EphA1 and P460L mutant EphA1 in AD is not fully understood. We have characterized this mutation biophysically and biochemically. Our structural in silico model and in vitro biochemical analysis demonstrate that EphA1-P460L mutation makes the receptor constitutively active suggesting a gain-of-toxic function leading to chronic EphA1 signaling in the brain. Moreover, we report that the EphA1 P460L variant triggers Rho-GTPase signaling dysregulation that could potentially contribute to spine morphology abnormalities and synaptic dysfunction observed in AD pathology.

show abstract

Section: Introductionsupporting

confidence: 56%

Alzheimer’s disease-associated P460L mutation in ephrin receptor type A1 (EphA1) leads to dysregulated Rho-GTPase signaling

Kim

Lasso

Patel

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The role of HSPGs in the prion-like spread of tau pathology has gained additional support in recent years from the analysis of tissues from the brains of patients with tauopathies and other forms of in vivo evidence. Two meta analyses of genome wide association studies for AD risk factors have implicated enhanced expression of the 3-O HS sulfotransferase gene Hs3st1 as an AD risk factor, supporting existing observations on the role of 3- O sulfated HS in tau protein uptake and phosphorylation ( Witoelar et al, 2018 ; Schwartzentruber et al, 2021 ). Consistent with in vitro work suggesting enhanced HS-tau binding promotes enhanced spread of tau pathology, Huynh et al (2019) have reported an increase in HS expression in the brains of patients with AD both in absolute terms and relative to chondroitin sulfate (CS), another member of the GAG family.…”

Section: Distinct Hs Sulfation Patterns Govern Tau-hs Interaction and Uptakesupporting

confidence: 61%

The Sulfation Code of Tauopathies: Heparan Sulfate Proteoglycans in the Prion Like Spread of Tau Pathology

Mah

Zhao

Zhang

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

Tauopathies are a heterogenous family of progressive neurodegenerative diseases defined by the appearance of proteinaceous lesions within the brain composed of abnormally folded species of Microtubule Associated Protein Tau (tau). Alzheimer’s Disease (AD), the most common tauopathy, is the leading cause of cognitive decline among the elderly and is responsible for more than half of all cases of senile dementia worldwide. The characteristic pathology of many tauopathies—AD included—presents as Neurofibrillary Tangles (NFTs), insoluble inclusions found within the neurons of the central nervous system composed primarily of tau protein arranged into Paired Helical Fibrils (PHFs). The spatial extent of this pathology evolves in a remarkably consistent pattern over the course of disease progression. Among the leading hypotheses which seek to explain the stereotypical progression of tauopathies is the prion model, which proposes that the spread of tau pathology is mediated by the transmission of self-propagating tau conformers between cells in a fashion analogous to the mechanism of communicable prion diseases. Protein-glycan interactions between tau and Heparan Sulfate Proteoglycans (HSPGs) have been implicated as a key facilitator in each stage of the prion-like propagation of tau pathology, from the initial secretion of intracellular tau protein into the extracellular matrix, to the uptake of pathogenic tau seeds by cells, and the self-assembly of tau into higher order aggregates. In this review we outline the biochemical basis of the tau-HS interaction and discuss our current understanding of the mechanisms by which these interactions contribute to the propagation of tau pathology in tauopathies, with a particular focus on AD.

show abstract

“…In contrast, significant enrichment (Bonferroni-corrected p-value < 0.05) of genes associated by common variant studies of Alzheimer's disease was identified only in microglia/macrophage cluster markers in the SNpc and striatum (Fig. 3A) 42,43 . Next, we tested for enrichment of disease risk gene expression across the 68 transcriptionally defined subpopulations (Methods).…”

Section: Enrichment Of Heritable Risk For Parkinson's Disease In the Degenerating Dopaminergic Subtypementioning

confidence: 93%

“…1B, Methods), to comprehensively profile all cell types in the SNpc. In total, we profiled 184,673 high-quality nuclei, 43.6% of which were from the NR4A2-positive cytometry gate (Methods, Fig. 1B).…”

Section: A Map Of Human Midbrain Dopaminergic Neuronsmentioning

confidence: 99%

A molecular census of midbrain dopaminergic neurons in Parkinson’s disease

Kamath

Abdulraouf

Burris

et al. 2021

Preprint

View full text Add to dashboard Cite

Midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) project widely throughout the central nervous system, playing critical roles in voluntary movements, reward processing, and working memory. Many of these neurons are highly sensitive to neurodegeneration in Parkinson's Disease (PD), and their loss correlates strongly with the pathognomonic symptoms. To characterize these populations molecularly, we developed a protocol to enrich and transcriptionally profile DA neuron nuclei from postmortem human SNpc of both PD patients and matched controls. We identified a total of ten distinct populations, including one that was primate-specific. A single subtype, marked by the gene AGTR1, was highly susceptible to degeneration, and was enriched for expression of genes associated with PD in genetic studies, suggesting many risk loci act within this subtype to influence its neurodegeneration. The AGTR1 subtype also showed the strongest upregulation of TP53 and its downstream targets, nominating a potential pathway of degeneration in vivo. The transcriptional characterization of differentially disease-vulnerable DA neurons in the SNpc will inform the development of laboratory models, enable the nomination of novel disease biomarkers, and guide further studies of pathogenic disease mechanisms.

show abstract

Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes

Cited by 328 publications

References 112 publications

Alzheimer’s disease-associated P460L mutation in ephrin receptor type A1 (EphA1) leads to dysregulated Rho-GTPase signaling

Alzheimer’s disease-associated P460L mutation in ephrin receptor type A1 (EphA1) leads to dysregulated Rho-GTPase signaling

The Sulfation Code of Tauopathies: Heparan Sulfate Proteoglycans in the Prion Like Spread of Tau Pathology

A molecular census of midbrain dopaminergic neurons in Parkinson’s disease

Contact Info

Product

Resources

About