On the causal role of retromer-dependent endosomal recycling in Alzheimer’s disease

Young, Jessica E.; Holstege, Henne; Andersen, Olav M.; Petsko, Gregory A.; Small, Scott A.

doi:10.1038/s41556-023-01245-2

Cited by 4 publications

(3 citation statements)

References 24 publications

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“…ABCA7*A1527G (rs3752246) is the most common of multiple predicted loss-of-function variants associated with increased LOAD risk at the ABCA7 locus (24,25). The SORL1*A528T (rs2298813) variant is among candidates in the SORL1 gene and likely involved in retromer function (26); deficits in retromer-dependent endosomal recycling have been implicated as causal in AD (27)(28)(29). The SNX1*D465N (rs1802376) variant locus is associated with AD (24) and SNX1 is involved in retromer function relevant to LOAD (30).…”

Section: Late-onset Ad Risk Variant Prioritizationmentioning

confidence: 99%

In vivovalidation of late-onset Alzheimer’s disease genetic risk factors

Sasner,

Preuss,

Pandey

et al. 2023

Preprint

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Structured AbstractIntroductionGenome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer’s disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action.MethodsCandidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE4 and Trem2*R47H. Potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts.ResultsWe created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes.DiscussionThese results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.

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Section: Late-onset Ad Risk Variant Prioritizationmentioning

confidence: 99%

In vivovalidation of late-onset Alzheimer’s disease genetic risk factors

Sasner,

Preuss,

Pandey

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…A more recent example, and one relevant to neurodegenerative diseases and the endo-lysosomal network, is provided by mutations in the Sortilin-Related Receptor 1 (SORL1), which has recently emerged as only the fourth gene that causes a rare, early-onset form of Alzheimer's disease [1,2]. Biological studies have first established that SORL1 triggers the disease by disrupting Retromer-dependent endosomal recycling, and second, have shown that this pathway can generalize to the common sporadic form of the disease (as reviewed in [3]).…”

Section: Introductionmentioning

confidence: 99%

Retromer-dependent lysosomal stress in Parkinson's disease

Alessi,

Cullen,

Cookson

et al. 2024

Phil. Trans. R. Soc. B

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While causative mutations in complex disorders are rare, they can be used to extract a biological pathway whose pathogenicity can generalize to common forms of the disease. Here we begin by relying on the biological consequences of mutations in LRRK2 and VPS35, genetic causes of autosomal-dominant Parkinson's disease, to hypothesize that ‘Retromer-dependent lysosomal stress’ represents a pathway that can generalize to idiopathic Parkinson's disease. Next, we outline a series of studies that can test this hypothesis, including the development of biomarkers of pathway dysfunction. If validated, the hypothesis can suggest a unified mechanism of disease and might inform future diagnostic and therapeutic investigations. This article is part of a discussion meeting issue ‘Understanding the endo-lysosomal network in neurodegeneration’.

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“…In parallel, genomic analysis of Alzheimer's disease, Parkinson's disease and related neurodegenerative disorders has identified that perturbation in these complexes and the endosomal pathway more generally is a common feature across these diseases [5,6]. A complementary series of studies in model systems have clarified the specific mechanisms of these genomic abnormalities.…”

mentioning

confidence: 99%

Understanding the endo-lysosomal network in neurodegeneration

Cullen,

Holstege,

Small

et al. 2024

Phil. Trans. R. Soc. B

Self Cite

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On the causal role of retromer-dependent endosomal recycling in Alzheimer’s disease

Cited by 4 publications

References 24 publications

In vivovalidation of late-onset Alzheimer’s disease genetic risk factors

In vivovalidation of late-onset Alzheimer’s disease genetic risk factors

Retromer-dependent lysosomal stress in Parkinson's disease

Understanding the endo-lysosomal network in neurodegeneration

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