High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

Pottier, Cyril; Hannequin, Didier; Coutant, Sophie; Rovelet‐Lecrux, Anne; Wallon, David; Rousseau, Stéphane; Legallic, Solenn; Paquet, Claire; Bombois, Stéphanie; Pariente, Jérémie; Thomas‐Antérion, Catherine; Michon, Agnès; Croisile, Bernard; Etcharry-Bouyx, Frédérique; Berr, Claudine; Jf, Dartigues; Amouyel, P.; Dauchel, Hélène; Boutoleau‐Bretonnière, Claire; Thauvin, Christel; Frébourg, Thierry; Lambert, J-C; Campion, Dominique

doi:10.1038/mp.2012.15

Cited by 261 publications

(246 citation statements)

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“…SORL1 encodes for the protein SorLA that belongs to a set of protein-trafficking molecules in the endocytic and retromer pathways and is implicated in modulating the production of Ab peptide [41]. These findings suggest that SORL1 may represent a genetic risk factor for AD, although these data need independent replication.…”

Section: Eofad With Mendelian Transmissionmentioning

confidence: 71%

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Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

105

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Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD

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Section: Eofad With Mendelian Transmissionmentioning

confidence: 71%

“…Recently, a study has detected mutations in the SORL1 gene in EOFAD patients [41]. SORL1 encodes for the protein SorLA that belongs to a set of protein-trafficking molecules in the endocytic and retromer pathways and is implicated in modulating the production of Ab peptide [41].…”

Section: Eofad With Mendelian Transmissionmentioning

confidence: 99%

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

105

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“…Results from histopathological and epidemiological studies further substantiate the crucial role of this receptor in sporadic AD. Equally exciting is a recent report that mutations in SORL1 might even be the cause of autosomal dominant forms of early-onset AD (Pottier et al, 2012). Here, five missense mutations, one of which maps to the APP binding domain in SORLA, have been identified in familial cases of AD.…”

Section: Discussionmentioning

confidence: 95%

Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

Willnow

Andersen

2013

Journal of Cell Science

102

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SummaryExcessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid b peptides (Ab) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.

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“…familial AD gene as well (11,26). Now, our studies identified the IR as a target for SORLA-mediated protein sorting in adipocytes.…”

Section: And H)mentioning

confidence: 95%

SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity

Schmidt

Schulz

Yan

et al. 2016

Journal of Clinical Investigation

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High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

Cited by 261 publications

References 10 publications

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity

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