SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease

Ma, Qing; Yang, Jianmin; Milner, Teresa A.; Vonsattel, Jean‐Paul; Palko, Mary Ellen; Tessarollo, Lino; Hempstead, Barbara L.

doi:10.1172/jci.insight.88995

Cited by 32 publications

(53 citation statements)

References 102 publications

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“…The NR2A subunit-containing NMDA receptors is also of importance for alcohol induced place preference (Boyce-Rustay and Holmes, 2006), and interestingly SorCS2 has been shown to regulate NMDAR trafficking by mediating surface trafficking of NR2A (Ma et al, 2017). Moreover, dysfunctions in NMDA receptor activity and plasticity have been observed in Sorcs2 −/− mice (Glerup et al, 2016), which may also contribute to the altered acute and adapted response to alcohol observed here (Ron and Barak, 2016).…”

Section: Discussionmentioning

confidence: 99%

Reduced Alcohol Seeking and Withdrawal Symptoms in Mice Lacking the BDNF Receptor SorCS2

et al. 2019

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Alcohol use disorder (AUD) is characterized by repetitive and uncontrolled intake of alcohol with severe consequences for affected individuals, their families and society as a whole. Numerous studies have implicated brain-derived neurotrophic factor (BDNF) activity in the neurobiology underlying AUD. The BDNF signaling mechanism is complex and depends on two receptor systems, TrkB and p75NTR, which appear to have opposite effects on alcohol seeking behavior in animal models. We recently discovered that the sortilin-related receptor SorCS2 forms complexes with both TrkB and p75NTR and is important for BDNF activity in the developing and adult CNS. Moreover, the SORCS2 gene was recently identified as the top association signal for severity of alcohol withdrawal symptoms. Hence, we speculated that SorCS2 deficient mice would have an altered response to alcohol. The role of SorCS2 in the acute and adapted response to alcohol was therefore investigated by comparing SorCS2 knockout ( Sorcs2 −/− ) mice to wild type (WT) mice in three paradigms modeling alcohol sensitivity and consumption; alcohol-induced conditioned place preference, two-bottle choice test as well as the behavioral response to alcohol withdrawal. We found that, when compared to the WT mice, (I) Sorcs2 −/− mice displayed complete lack of alcohol-induced place preference, (II) when given free choice between water and alcohol, Sorcs2 −/− mice consumed less alcohol, and (III) Sorcs2 −/− mice showed no handling-induced convulsion in response to alcohol withdrawal following extended alcohol exposure. Taken together, these results show that lack of the alcohol withdrawal risk gene Sorcs2 results in abnormal behavioral response to alcohol in mice. Consequently, SorCS2 may play an important role in the molecular pathways underlying AUD and complications associated with alcohol withdrawal.

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Section: Discussionmentioning

confidence: 99%

Reduced Alcohol Seeking and Withdrawal Symptoms in Mice Lacking the BDNF Receptor SorCS2

et al. 2019

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“…In summary, we identified a novel molecular mechanism of SorCS2 action in neurons that is of major relevance for brain pathophysiology. This newly discovered role in sorting of EAAT3 complements other neuronal activities of this multifunctional receptor, such as sorting of NMDA receptors (Ma et al, 2017) or regulation of signaling by the proforms of brain derived neurotrophic factor (Anastasia et al, 2013;Glerup et al, 2014Glerup et al, , 2016 and nerve growth factor (Deinhardt et al, 2011). Likely, impairement of SorCS2 activity results in alterations of multiple neuronal sorting processes, collectively contributing to various brain pathologies associated with this receptor.…”

Section: Discussionmentioning

confidence: 88%

“…Futhermore, aberrant localization of EAAT3 was noted in the brain of Alzheimer's disease patients, particularly in CA2 (Duerson et al, 2009). Finally, in mouse models of Huntington's disease impaired SorCS2 function was observed (Ma et al, 2017), as well as aberrant EAAT3 localization leading to increased levels of oxidative stress (Li et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

SorCS2 controls functional expression of amino acid transporter EAAT3 to protect neurons from oxidative stress and epilepsy-induced pathology

Malik

Szydłowska

Nizinska

et al. 2018

Preprint

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The family of VPS10P domain receptors emerges as central regulator of intracellular protein sorting in neurons with relevance for various brain pathologies. Here, we identified a unique role for the family member SorCS2 in protection of neurons from oxidative stress and from epilepsy-induced cell death. We show that SorCS2 acts as sorting receptor that targets the neuronal amino acid transporter EAAT3 to the plasma membrane to facilitate import of cysteine, required for synthesis of the reactive oxygen species scavenger glutathione. Absence of SorCS2 activity causes aberrant transport of EAAT3 to lysosome for catabolism and impairs cysteine uptake. As a consequence, SorCS2-deficient mice exhibit oxidative brain damage that coincides with enhanced neuronal cell death and increased mortality during epilepsy. Our findings highlight a protective role for SorCS2 in neuronal stress response and provide an explanation for upregulation of the receptor seen in surviving neurons of the human epileptic brain.

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“…Members of the VPS10p family have been shown to play an important role in synaptic plasticity 4 , 5 , 37 , 38 and have been associated with neurodegenerative diseases such as Alzheimer’s 39 , 40 , frontotemporal lobar degeneration 41 and Huntington’s 2 , and psychological disorders such as schizophrenia, bipolar disorders, and attention-deficit hyperactivity disorder 42 – 44 . Since its structure was first solved, Sortilin has been the target for design of small-molecules inhibitors, in hopes that modulating its receptor function would offer therapeutic applications 45 , 46 .…”

Section: Discussionmentioning

confidence: 99%

“…The type I transmembrane receptor Sortilin-related CNS-expressed receptor 2 (SorCS2), together with SorCS1 and 3, Sortilin and SorLA constitute the Vacuolar Protein Sorting 10 protein (VPS10p) family that is central to many pathways in control of neuronal viability and function, and has been associated with cancer and neurodegenerative diseases such as Alzheimer’s 1 and Huntington’s 2 . Two roles have been identified for VPS10p members; in particular, SorCS2 and Sortilin are well studied for their function as extracellular receptors for the cognate proneurotrophin ligands to regulate synaptic plasticity and trigger apoptotic signaling 3 – 6 , and they are responsible for binding and sorting a diverse set of ligands for secretion, internalization and endosome to lysosome sorting 7 – 9 .…”

Section: Introductionmentioning

confidence: 99%

Structural insights into SorCS2–Nerve Growth Factor complex formation

2018

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Signaling of SorCS receptors by proneurotrophin ligands regulates neuronal plasticity, induces apoptosis and is associated with mental disorders. The detailed structure of SorCS2 and its extracellular specificity are unresolved. Here we report crystal structures of the SorCS2–NGF complex and unliganded SorCS2 ectodomain, revealing cross-braced SorCS2 homodimers with two NGF dimers bound in a 2:4 stoichiometry. Five out of six SorCS2 domains directly contribute to dimer formation and a C-terminal membrane proximal unreported domain, with an RNA recognition motif fold, locks the dimer in an intermolecular head-to-tail interaction. The complex structure shows an altered SorCS2 conformation indicating substantial structural plasticity. Both NGF dimer chains interact exclusively with the top face of a SorCS2 β-propeller. Biophysical experiments reveal that NGF, proNGF, and proBDNF bind at this site on SorCS2. Taken together, our data reveal a structurally flexible SorCS2 receptor that employs the large β-propeller as a ligand binding platform.

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SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease

Cited by 32 publications

References 102 publications

Reduced Alcohol Seeking and Withdrawal Symptoms in Mice Lacking the BDNF Receptor SorCS2

Reduced Alcohol Seeking and Withdrawal Symptoms in Mice Lacking the BDNF Receptor SorCS2

SorCS2 controls functional expression of amino acid transporter EAAT3 to protect neurons from oxidative stress and epilepsy-induced pathology

Structural insights into SorCS2–Nerve Growth Factor complex formation

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