Michelle E Ehrlich

Icahn School of Medicine at Mount Sinai, Borough of Manhattan, New York, United States

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Publications (87)554.64 Total impact


  • No preview · Article · Jan 2016
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    ABSTRACT: In the striatum, signaling via G protein-coupled neurotransmitter receptors is essential for motor control. Critical to this process is the effector enzyme adenylyl cyclase type 5 (AC5) that produces second messenger cAMP upon receptor-mediated activation by G protein G olf . However, the molecular organization of the G olf -AC5 signaling axis is not well understood. In this study, we report that in the striatum AC5 exists in a stable pre-coupled complex with subunits of Golf heterotrimer. We use genetic mouse models with disruption in individual components of the complex to reveal hierarchical order of interactions required for AC5-G olf stability. We further identify that the assembly of AC5-G olf complex is mediated by PhLP1 chaperone that plays central role in neurotransmitter receptor coupling to cAMP production motor learning. These findings provide evidence for the existence of stable G protein-effector signaling complexes and identify a new component essential for their assembly.
    No preview · Article · Nov 2015 · eLife Sciences
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    ABSTRACT: The presenilin 1 (PSEN1) L271V mutation causes early-onset familial Alzheimer’s disease by disrupting the alternative splicing of the PSEN1 gene, producing some transcripts harboring the L271V point mutation and other transcripts lacking exon 8 (PS1∆exon8). We previously reported that PS1 L271V increased amyloid beta (Aβ) 42/40 ratios, while PS1∆exon8 reduced Aβ42/40 ratios, indicating that the former and not the exon 8 deletion transcript is amyloidogenic. Also, PS1∆exon8 did not rescue Aβ generation in PS1/2 double knockout cells indicating its identity as a severe loss-of-function splice form. PS1∆exon8 is generated physiologically raising the possibility that we had identified the first physiological inactive PS1 isoform. We studied PS1∆exon8 in vivo by crossing PS1∆exon8 transgenics with either PS1-null or Dutch APPE693Q mice. As a control, we crossed APPE693Q with mice expressing a deletion in an adjacent exon (PS1∆exon9). PS1∆exon8 did not rescue embryonic lethality or Notch-deficient phenotypes of PS1-null mice displaying severe loss of function in vivo. We also demonstrate that this splice form can interact with wildtype PS1 using cultured cells and co-immunoprecipitation (co-IP)/bimolecular fluorescence complementation. Further co-IP demonstrates that PS1∆exon8 interacts with nicastrin, participating in the γ–secretase complex formation. These data support that catalytically inactive PS1∆exon8 is generated physiologically and participates in protein-protein interactions.
    Full-text · Article · Nov 2015 · Scientific Reports
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    ABSTRACT: Identification and characterization of molecular mechanisms that connect genetic risk factors to initiation and evolution of disease pathophysiology represent major goals and opportunities for improving therapeutic and diagnostic outcomes in Alzheimer's disease (AD). Integrative genomic analysis of the human AD brain transcriptome holds potential for revealing novel mechanisms of dysfunction that underlie the onset and/or progression of the disease. We performed an integrative genomic analysis of brain tissue-derived transcriptomes measured from two lines of mice expressing distinct mutant AD-related proteins. The first line expresses oligomerogenic mutant APP(E693Q) inside neurons, leading to the accumulation of amyloid beta (Aβ) oligomers and behavioral impairment, but never develops parenchymal fibrillar amyloid deposits. The second line expresses APP(KM670/671NL)/PSEN1(Δexon9) in neurons and accumulates fibrillar Aβ amyloid and amyloid plaques accompanied by neuritic dystrophy and behavioral impairment. We performed RNA sequencing analyses of the dentate gyrus and entorhinal cortex from each line and from wild-type mice. We then performed an integrative genomic analysis to identify dysregulated molecules and pathways, comparing transgenic mice with wild-type controls as well as to each other. We also compared these results with datasets derived from human AD brain. Differential gene and exon expression analysis revealed pervasive alterations in APP/Aβ metabolism, epigenetic control of neurogenesis, cytoskeletal organization and extracellular matrix (ECM) regulation. Comparative molecular analysis converged on FMR1 (Fragile X Mental Retardation 1), an important negative regulator of APP translation and oligomerogenesis in the post-synaptic space. Integration of these transcriptomic results with human postmortem AD gene networks, differential expression and differential splicing signatures identified significant similarities in pathway dysregulation, including ECM regulation and neurogenesis, as well as strong overlap with AD-associated co-expression network structures. The strong overlap in molecular systems features supports the relevance of these findings from the AD mouse models to human AD.Molecular Psychiatry advance online publication, 10 November 2015; doi:10.1038/mp.2015.167.
    Preview · Article · Nov 2015 · Molecular Psychiatry
  • Cesar L Moreno · Michelle E Ehrlich · Charles V Mobbs
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    ABSTRACT: Huntington's disease (HD) is a fatal neurodegenerative disease characterized by metabolic, cognitive, and motor deficits. HD is caused by an expanded CAG repeat in the first exon of the HTT gene, resulting in an expanded polyglutamine section. Dietary restriction (DR) increases lifespan and ameliorates age-related pathologies, including in a model of HD, but the mechanisms mediating these protective effects are unknown. We report metabolic and behavioral effects of DR in the full-length YAC128 HD mouse model, and associated transcriptional changes in hypothalamus and striatum. DR corrected many effects of the transgene including increased body weight, decreased blood glucose, and impaired motor function. These changes were associated with reduced striatal human (but not mouse) HTT expression, as well as alteration in gene expression regulating histone acetylation modifications, particularly Hdac2. Other mRNAs related to Huntington's pathology in striatal tissue showed significant modulation by the transgene, dietary restriction or both. These results establish a protective role of DR in a transgenic model that contains the complete human HTT gene and for the first time suggest a role for DR in lowering HTT level, which correlates with severity of symptoms.
    No preview · Article · Oct 2015 · Neurobiology of Disease
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    ABSTRACT: DYT6 dystonia is caused by mutations in THAP1 [Thanatos-associated (THAP) domain-containing apoptosis-associated protein] and is autosomal dominant and partially penetrant. Like other genetic primary dystonias, DYT6 patients have no characteristic neuropathology, and mechanisms by which mutations in THAP1 cause dystonia are unknown. Thap1 is a zinc-finger transcription factor, and most pathogenic THAP1 mutations are missense and are located in the DNA-binding domain. There are also nonsense mutations, which act as the equivalent of a null allele because they result in the generation of small mRNA species that are likely rapidly degraded via nonsense-mediated decay. The function of Thap1 in neurons is unknown, but there is a unique, neuronal 50-kDa Thap1 species, and Thap1 levels are auto-regulated on the mRNA level. Herein, we present the first characterization of two mouse models of DYT6, including a pathogenic knockin mutation, C54Y and a null mutation. Alterations in motor behaviors, transcription and brain structure are demonstrated. The projection neurons of the deep cerebellar nuclei are especially altered. Abnormalities vary according to genotype, sex, age and/or brain region, but importantly, overlap with those of other dystonia mouse models. These data highlight the similarities and differences in age- and cell-specific effects of a Thap1 mutation, indicating that the pathophysiology of THAP1 mutations should be assayed at multiple ages and neuronal types and support the notion of final common pathways in the pathophysiology of dystonia arising from disparate mutations.
    No preview · Article · Sep 2015 · Human Molecular Genetics
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    ABSTRACT: D1-dopamine receptors (Drd1a) are highly expressed in the deep layers of the cerebral cortex and the striatum. A number of human diseases such as Huntington disease and schizophrenia are known to have cortical pathology involving dopamine receptor expressing neurons. To illuminate their functional role, we exploited a Cre/Lox molecular paradigm to generate Emx-1(tox) MUT mice, a transgenic line in which cortical Drd1a-expressing pyramidal neurons were selectively ablated. Emx-1(tox) MUT mice displayed prominent forelimb dystonia, hyperkinesia, ataxia on rotarod testing, heightened anxiety-like behavior, and age-dependent abnormalities in a test of social interaction. The latter occurred in the context of normal working memory on testing in the Y-maze and for novel object recognition. Some motor and behavioral abnormalities in Emx-1(tox) MUT mice overlapped with those in CamKIIα(tox) MUT transgenic mice, a line in which both striatal and cortical Drd1a-expressing cells were ablated. Although Emx-1(tox) MUT mice had normal striatal anatomy, both Emx-1(tox) MUT and CamKIIα(tox) MUT mice displayed selective neuronal loss in cortical layers V and VI. This study shows that loss of cortical Drd1a-expressing cells is sufficient to produce deficits in multiple motor and behavioral domains, independent of striatal mechanisms. Primary cortical changes in the D1 dopamine receptor compartment are therefore likely to model a number of core clinical features in disorders such as Huntington disease and schizophrenia. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Feb 2015 · Neurobiology of Disease

  • No preview · Article · Jan 2015 · Drug and Alcohol Dependence
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    ABSTRACT: Certain mutant Alzheimer’s amyloid-β (Aβ) peptides (that is, Dutch mutant APPE693Q) form complexes with gangliosides (GAβ). These mutant Aβ peptides may also undergo accelerated aggregation and accumulation upon exposure to GM2 and GM3. We hypothesized that increasing β-hexosaminidase (β-hex) activity would lead to a reduction in GM2 levels, which in turn, would cause a reduction in Aβ aggregation and accumulation. The small molecule OT1001 is a β-hex-targeted pharmacological chaperone with good bioavailability, blood–brain barrier penetration, high selectivity for β-hex and low cytotoxicity. Dutch APPE693Q transgenic mice accumulate oligomeric Aβ as they age, as well as Aβ oligomer-dose-dependent anxiety and impaired novel object recognition (NOR). Treatment of Dutch APPE693Q mice with OT1001 caused a dose-dependent increase in brain β-hex levels up to threefold over those observed at baseline. OT1001 treatment was associated with reduced anxiety, improved learning behavior in the NOR task and dramatically reduced GAβ accumulation in the subiculum and perirhinal cortex, both of which are brain regions required for normal NOR. Pharmacological chaperones that increase β-hex activity may be useful in reducing accumulation of certain mutant species of Aβ and in preventing the associated behavioral pathology.
    Full-text · Article · Oct 2014 · Molecular Psychiatry
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    ABSTRACT: Mounting evidence suggests that soluble oligomers of amyloid-β (oAβ) represent the pertinent synaptotoxic form of Aβ in sporadic Alzheimer’s disease (AD); however, the mechanistic links between oAβ and synaptic degeneration remain elusive. Most in vivo experiments to date have been limited to examining the toxicity of oAβ in mouse models that also possess insoluble fibrillar Aβ (fAβ), and data generated from these models can lead to ambiguous interpretations. Our goal in the present study was to examine the effects of soluble oAβ on neuronal and synaptic structure in the amyloid precursor protein (APP) E693Q (“Dutch”) mouse model of AD, which develops intraneuronal accumulation of soluble oAβ with no detectable plaques in AD-relevant brain regions. We performed quantitative analyses of neuronal pathology, including dendrite morphology, spine density, and synapse ultrastructure in individual hippocampal CA1 neurons. When assessing neuronal morphology and complexity we observed significant alterations in apical but not in basal dendritic arbor length in Dutch mice compared to wild type. Moreover, Dutch mice exhibited a significant decrease in dendritic arborization with a decrease in dendritic length and number of intersections at 120 μm and 150 μm from the soma, respectively. We next examined synaptic parameters and found that while there were no differences in overall synaptic structure, Dutch mice displayed a significant reduction in the post-synaptic density (PSD) length of synapses on mushroom spines, in comparison to wild type littermates. The structural alterations to individual neurons in Dutch mice along with the changes in larger dendritic spines support the Aβ oligomer hypothesis, which postulates that the early cognitive impairments that occur in AD are attributed to the accumulation of soluble oAβ first affecting at the synaptic level with subsequent structural disturbances and cellular degeneration.
    Full-text · Article · Oct 2014 · Molecular Neurodegeneration
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    ABSTRACT: Mutations in THAP1 result in dystonia type 6, with partial penetrance and variable phenotype. The goal of this study was to examine the nature and expression pattern of the protein product(s) of the Thap1 transcription factor (DYT6 gene) in mouse neurons, and to study the regional and developmental distribution, and subcellular localization of Thap1 protein. The goal was accomplished via overexpression and knock-down of Thap1 in the HEK293T cell line and in mouse striatal primary cultures and western blotting of embryonic Thap1-null tissue. The endogenous and transduced Thap1 isoforms were characterized using three different commercially available anti-Thap1 antibodies and validated by immunoprecipitation and DNA oligonucleotide affinity chromatography. We identified multiple, novel Thap1 species of apparent Mr 32 kDa, 47 kDa, and 50¿52 kDa in vitro and in vivo, and verified the previously identified species at 29¿30 kDa in neurons. The Thap1 species at the 50 kDa size range was exclusively detected in murine brain and testes and were located in the nuclear compartment. Thus, in addition to the predicted 25 kDa apparent Mr, we identified Thap1 species with greater apparent Mr that we speculate may be a result of posttranslational modifications. The neural localization of the 50 kDa species and its nuclear compartmentalization suggests that these may be key Thap1 species controlling neuronal gene transcription. Dysfunction of the neuronal 50 kDa species may therefore be implicated in the pathogenesis of DYT6.
    Full-text · Article · Sep 2014
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    ABSTRACT: Proneurogenic compounds have recently shown promise in some mouse models of Alzheimer's pathology. Antagonists at Group II metabotropic glutamate receptors (Group II mGluR: mGlu2, mGlu3) are reported to stimulate neurogenesis. Agonists at those receptors trigger γ-secretase-inhibitor-sensitive biogenesis of Aβ42 peptides from isolated synaptic terminals, which is selectively suppressed by antagonist pretreatment. We have assessed the therapeutic potential of chronic pharmacological inhibition of Group II mGluR in Dutch APP (Alzheimer's amyloid precursor protein E693Q) transgenic mice that accumulate Dutch amyloid-β (Aβ) oligomers but never develop Aβ plaques. BCI-838 is a clinically well-tolerated, orally bioavailable, investigational prodrug that delivers to the brain BCI-632, the active Group II mGluR antagonist metabolite. Dutch Aβ-oligomer-forming APP transgenic mice (APP E693Q) were dosed with BCI-838 for 3 months. Chronic treatment with BCI-838 was associated with reversal of transgene-related amnestic behavior, reduction in anxiety, reduction in levels of brain Aβ monomers and oligomers, and stimulation of hippocampal neurogenesis. Group II mGluR inhibition may offer a unique package of relevant properties as an Alzheimer's disease therapeutic or prophylactic by providing both attenuation of neuropathology and stimulation of repair.Molecular Psychiatry advance online publication, 12 August 2014; doi:10.1038/mp.2014.87.
    Full-text · Article · Aug 2014 · Molecular Psychiatry
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    ABSTRACT: The high affinity tyrosine kinase receptor, TrkB, is the primary receptor for brain derived neurotrophic factor (BDNF) and plays an important role in development, maintenance and plasticity of the striatal output medium size spiny neuron. The striatal BDNF/TrkB system is thereby implicated in many physiologic and pathophysiologic processes, the latter including mood disorders, addiction, and Huntington's disease. We crossed a mouse harboring a transgene directing cre-recombinase expression primarily to postnatal, dorsal striatal medium spiny neurons, to a mouse containing a floxed TrkB allele (fB) mouse designed for deletion of TrkB to determine its role in the adult striatum. We found that there were sexually dimorphic alterations in behaviors in response to stressful situations and drugs of abuse. Significant sex and/or genotype differences were found in the forced swim test of depression-like behaviors, anxiety-like behaviors on the elevated plus maze, and cocaine conditioned reward. Microarray analysis of dorsal striatum revealed significant dysregulation in individual and groups of genes that may contribute to the observed behavioral responses and in some cases, represent previously unidentified downstream targets of TrkB. The data point to a set of behaviors and changes in gene expression following postnatal deletion of TrkB in the dorsal striatum distinct from those in other brain regions.
    Full-text · Article · Dec 2013 · Molecular Neurodegeneration
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    ABSTRACT: Neurotrophins and modifiers of chromatin acetylation and deacetylation participate in regulation of transcription during neuronal maturation and maintenance. The striatal medium spiny neuron is supported by cortically-derived brain derived neurotrophic factor and is the most vulnerable neuron in Huntington's disease, in which growth factor and histone deacetylase activity are both disrupted. We examined the ability of three histone deacetylase inhibitors, trichostatin A, valproic acid and Compound 4 b, alone and combined with brain derived neurotrophic factor (BDNF), to promote phenotypic maturation of striatal medium spiny neurons in vitro. Exposure of these neurons to each of the three compounds led to an increase in overall histone H3 and H4 acetylation, dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa (DARPP-32) mRNA and protein, and mRNA levels of other markers of medium spiny neuron maturation. We were, however, unable to prove that HDAC inhibitors directly lead to remodeling of Ppp1r1b chromatin. In addition, induction of DARPP-32 by brain-derived neurotrophic factor was inhibited by histone deacetylase inhibitors. Although BDNF-induced increases in pTrkB, pAkt, pERK and Egr-1 were unchanged by combined application with VPA, the increase in DARPP-32 was relatively diminished. Strikingly, the NGF1A-binding protein, Nab2, was induced by BDNF, but not in the presence of VPA or TSA. Gel shift analysis showed that α-Nab2 super-shifted a band that is more prominent with extract derived from BDNF-treated neurons than with extracts from cultures treated with VPA alone or VPA plus BDNF. In addition, overexpression of Nab2 induced DARPP-32. We conclude that histone deacetylase inhibitors inhibit the induction of Nab2 by BDNF, and thereby the relative induction of DARPP-32.
    Full-text · Article · Oct 2013 · PLoS ONE
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    ABSTRACT: Progressive cell loss is observed in the striatum, cerebral cortex, thalamus, hypothalamus, subthalamic nucleus and hippocampus in Huntington disease. In the striatum, dopamine-responsive medium spiny neurons are preferentially lost. Clinical features include involuntary movements, gait and orofacial impairments in addition to cognitive deficits and psychosis, anxiety and mood disorders. We utilized the Cre-LoxP system to generate mutant mice with selective postnatal ablation of D1 dopamine receptor-expressing striatal neurons to determine which elements of the complex Huntington disease phenotype relate to loss of this neuronal subpopulation. Mutant mice had reduced bodyweight, locomotor slowing, reduced rearing, ataxia, a short stride length wide-based erratic gait, impairment in orofacial movements and displayed haloperidol-suppressible tic-like movements. The mutation was associated with an anxiolytic profile. Mutant mice had significant striatal-specific atrophy and astrogliosis. D1-expressing cell number was reduced throughout the rostrocaudal extent of the dorsal striatum consistent with partial destruction of the striatonigral pathway. Additional striatal changes included up-regulated D2 and enkephalin mRNA, and an increased density of D2 and preproenkephalin-expressing projection neurons, and striatal neuropeptide Y and cholinergic interneurons. These data suggest that striatal D1-cell-ablation alone may account for the involuntary movements and locomotor, balance and orofacial deficits seen not only in HD but also in HD phenocopy syndromes with striatal atrophy. Therapeutic strategies would therefore need to target striatal D1 cells to ameliorate deficits especially when the clinical presentation is dominated by a bradykinetic/ataxic phenotype with involuntary movements.
    Full-text · Article · Oct 2013 · Neurobiology of Disease
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    ABSTRACT: Mice generated by a Cre/LoxP transgenic paradigm were used to model neurodegenerative basal ganglia disease of which Huntington disease (HD) is the prototypical example. In HD, death occurs in striatal projection neurons as well as cortical neurons. Cortical and striatal neurons that express the D1 dopamine receptor (Drd1a) degenerate in HD. The contribution that death of specific neuronal cell populations makes to the HD disease phenotype and the response of the brain to loss of defined cell subtypes is largely unknown. Drd1a-expressing cells were targeted for cell death and three independent lines generated; a striatal-restricted line, a cortical-restricted line and a global line in which Drd1a cells were deleted from both the striatum and cortex. Two independent experimental approaches were used. In the first, the proliferative marker Ki-67 was used to identify proliferating cells in eighty-week-old mice belonging to a generic global line, a global in which Drd1a cells express green fluorescent protein (GFP-global) and in eighty-week-old mice of a cortical line. In the second experiment, the proliferative response of four-week-old mice belonging to GFP-global and striatal lines was assessed using the thymidine analogue BrdU. The phenotype of proliferating cells was ascertained by double staining for BrdU and Olig2 (an oligodendrocyte marker), Iba1 (a microglial cell marker), S100beta (an astroglial cell marker), or NeuN (a neuronal cell marker). In the first study, we found that Ki-67-expressing cells were restricted to the striatal side of the lateral ventricles. Control mice had a greater number of Ki-67+ cells than mutant mice. There was no overlap between Ki-67 and GFP staining in control or mutant mice, suggesting that cells did not undergo cell division once they acquired a Drd1a phenotype. In contrast, in the second study we found that BrdU+ cells were identified throughout the cortex, striatum and periventricular region of control and mutant mice. Mutant mice from the GFP-global line showed increased BrdU+ cells in the cortex, striatum and periventricular region relative to control. Striatal line mutant mice had an increased number of BrdU+ cells in the striatum and periventricular region, but not the cortex. The number of microglia, astrocytes, oligodendrocytes and neurons generated from dividing progenitors was increased relative to control mice in most brain regions in mutant mice from the GFP-global line. In contrast, striatal line mutant mice displayed an increase only in the number of dividing microglia in striatal and periventricular regions. Genetically programmed post-natal ablation of Drd1a-expressing neurons is associated with an extensive proliferative response involving multiple cell lineages. The nature of the tissue response has the potential not only to remove cellular debris but also to forge physiologically meaningful brain repair. Age related deficits in proliferation are seen in mutant lines. A blunted endogenous reparative response may underlie the cumulative deficits characteristic of age related neurodegeneration.
    Full-text · Article · Oct 2013 · BMC Neuroscience
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    ABSTRACT: Recent studies have linked synaptojanin 1 (synj1), the main phosphoinositol (4,5) biphosphate phosphatase [PI(4,5)P2 degrading enzyme] in the brain and synapses (1), to AD (2,3). Here we report a novel mechanism by which synj1 reversely regulates cellular clearance of Abeta. Genetic down-regulation of synj1 expression reduces both extracellular and intracellular Abeta levels in N2a cells stably expressing the Swedish mutant of APP. Moreover, synj1 haploinsufficiency in an AD transgenic mouse model expressing the Swedish mutant APP and the presenilin-1 (PS1) mutant deltaE9 reduces amyloid plaque load, as well as Abeta40 and Abeta42 levels in hippocampal regions of 9-month old animals. Reduced expression of synj1 attenuates cognitive deficits in these transgenic mice. However, reduction of synj1 does not affect levels of holoAPP and betaCTF, suggesting that Abeta generation by beta- and gamma-secretase cleavage is not affected. Instead, synj1 knockdown increases Abeta uptake and cellular degradation through accelerated delivery to lysosomes. These effects are partially dependent upon elevated PI(4,5)P2 with synj1 down-regulation. In summary, these data suggest a novel mechanism by which reduction of a PI(4,5)P2 degrading enzyme, synj1 improves amyloid induced neuropathology and behavior deficits through accelerating cellular Abeta clearance.
    No preview · Article · Sep 2013 · Journal of Biological Chemistry
  • Elysse Knight · Paul Szabo · Michelle Ehrlich · Norman Relkin · Sam Gandy

    No preview · Article · Jul 2013 · Alzheimer's and Dementia
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    Rachel F Lane · John W Steele · Dongming Cai · Michelle E Ehrlich · Alan D Attie · Sam Gandy
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    ABSTRACT: Endosomal sorting of the Alzheimer amyloid precursor protein (APP) plays a key role in the biogenesis of the amyloid-β (Aβ) peptide. Genetic lesions underlying Alzheimer's disease (AD) can act by interfering with this physiological process. Specifically, proteins involved in trafficking between endosomal compartments and the trans-Golgi network (TGN) [including the retromer complex (Vps35, Vps26) and its putative receptors (sortilin, SorL1, SorCS1)] have been implicated in the molecular pathology of late-onset AD. Previously, we demonstrated a role for SorCS1 in APP metabolism and Aβ production and, while we implicated a role for the retromer in this regulation, the underlying mechanism remained poorly understood. Here, we provide evidence for a motif within the SorCS1c cytoplasmic tail that, when manipulated, results in perturbed sorting of APP and/or its fragments to endosomal compartments, decreased retrograde TGN trafficking, and increased Aβ production in H4 neuroglioma cells. These perturbations apparently do not involve turnover of the cell surface APP pool, but rather they involve intracellular APP and/or its fragments, downstream of APP endocytosis.
    Full-text · Article · Apr 2013 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures. Its molecular pathophysiology is poorly understood, in part owing to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1), THAP1 (DYT6) and CIZ1 (ref. 5), have been identified. Using exome sequencing in two families with PTD, we identified a new causative gene, GNAL, with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encoding p.Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays.
    Full-text · Article · Dec 2012 · Nature Genetics

Publication Stats

2k Citations
554.64 Total Impact Points

Institutions

  • 2008-2015
    • Icahn School of Medicine at Mount Sinai
      • • Department of Neurology
      • • Department of Pediatrics
      Borough of Manhattan, New York, United States
    • University of Utah
      Salt Lake City, Utah, United States
  • 2005-2012
    • Thomas Jefferson University
      • • Farber Institute for Neurosciences
      • • Department of Neurology
      Filadelfia, Pennsylvania, United States
  • 2011
    • James J. Peters VA Medical Center
      New York, New York, United States
  • 2010
    • Mount Sinai Medical Center
      New York, New York, United States
  • 2004-2010
    • Thomas Jefferson University Hospitals
      • Department of Neurology
      Philadelphia, Pennsylvania, United States
    • University of Toronto
      Toronto, Ontario, Canada
  • 1998-2004
    • Nathan Kline Institute
      Orangeburg, New York, United States
  • 1996-2002
    • CUNY Graduate Center
      New York, New York, United States