A truncating mutation in Alzheimer's disease inactivates neuroligin-1 synaptic function

Tristán-Clavijo, Enriqueta; Camacho-Garcia, Rafael J.; Robles-Lanuza, Estefanía; Ruiz, Agustín; Zee, Julie van der; Broeckhoven, Christine Van; Hernández, Isabel; Martı́nez-Mir, Amalia; Scholl, Francisco G.

doi:10.1016/j.neurobiolaging.2015.09.004

Cited by 25 publications

(28 citation statements)

References 31 publications

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“…The regulation of these long neuronal genes is further complicated by intricate splicing dynamics 50,51 , which require highly dynamic and adaptive responses based on neuronal activation state. It is therefore not surprising that for many of these long genes, including for Nrxn3, Rbfox1 and Nlgn1, genetic variants are often associated with or directly result in neuronal diseases [60][61][62] . Thus, understanding how genome folding relates with the response to environmental challenges is increasingly important to further our understanding of the mechanisms of neurological disease.…”

Section: Discussionmentioning

confidence: 99%

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

Winick-Ng

Kukalev

Harabula

et al. 2020

Preprint

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Neurons and oligodendrocytes are terminally differentiated cells that perform highly specialized functions, which depend on cascades of gene activation and repression to retain homeostatic control over a lifespan. Gene expression is regulated by threedimensional (3D) genome organisation, from local levels of chromatin compaction to the organisation of topological domains and chromosome compartments. Whereas our understanding of 3D genome architecture has vastly increased in the past decade, it remains difficult to study specialized cells in their native environment without disturbing their activity. To develop the application of Genome Architecture Mapping (GAM) in small numbers of specialized cells in complex tissues, we combined GAM with immunoselection. We applied immunoGAM to map the genome architecture of specific cell populations in the juvenile/adult mouse brain: dopaminergic neurons (DNs) from the midbrain, pyramidal glutamatergic neurons (PGNs) from the hippocampus, and oligodendrocyte lineage cells (OLGs) from the cortex. We integrate 3D genome organisation with single-cell transcriptomics data, and find specific chromatin structures that relate with cell-type specific patterns of gene expression. We discover abundant changes in compartment organisation, especially a strengthening of heterochromatin compartments which establish strong contacts spanning tens of megabases, especially in brain cells. These compartments contain olfactory and taste receptor genes, which are de-repressed in a subpopulation of PGNs with molecular signatures of long-term potentiation (LTP). We also show extensive reorganisation of topological domains where activation of neuronal or oligodendrocyte genes coincides with formation of new TAD borders.Finally, we discover loss of TAD organisation, or 'TAD melting', at long (>1Mb) neuronal genes when they are most highly expressed. Our work shows that the 3D 3 organisation of the genome is highly cell-type specific in terminally differentiated cells of the brain, and essential to better understand brain-specific mechanisms of gene regulation.

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Section: Discussionmentioning

confidence: 99%

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

Winick-Ng

Kukalev

Harabula

et al. 2020

Preprint

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“…These data suggest that NL1 can promote the targeting of A β oligomers to the postsynaptic sites of excitatory synapses and thereby promotes synaptic toxicity in AD. A mutation in the NL1 gene was found in AD patients, generating a premature stop codon in the extracellular domain of NL1 (p.Thr271fs) that blocks the function of NL1 and thus its ability to form glutamatergic synapses [113]. Interestingly, in a neuroinflammation rodent model induced by hippocampal injections of A β 1–40 , there was a decrease in NL1 expression with subsequent impairment of synaptic function and memory [227, 228].…”

Section: Postsynaptic Proteinsmentioning

confidence: 99%

Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

2017

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Synapses are complex structures that allow communication between neurons in the central nervous system. Studies conducted in vertebrate and invertebrate models have contributed to the knowledge of the function of synaptic proteins. The functional synapse requires numerous protein complexes with specialized functions that are regulated in space and time to allow synaptic plasticity. However, their interplay during neuronal development, learning, and memory is poorly understood. Accumulating evidence links synapse proteins to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. In this review, we describe the way in which several proteins that participate in cell adhesion, scaffolding, exocytosis, and neurotransmitter reception from presynaptic and postsynaptic compartments, mainly from excitatory synapses, have been associated with several synaptopathies, and we relate their functions to the disease phenotype.

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“…Presynaptic neurexin2a (NRXN2a) and the postsynaptic adhesion protein, neuroligin1 (NLGN1), interact trans-synaptically to ensure structural stability and functions of excitatory synapses in the hippocampus and cortex (6,7). NLGN1 and NRXN2a both bind synaptotoxic Ab peptide oligomers to increase their synaptic concentrations, thereby enhancing oxidative stress and promoting synaptic damage in AD (15)(16)(17). Cognitive loss induced by the administration of Ab peptide oligomers to mice is lessened by concurrent doses of Abs to NLGN1 and NRXN2a that diminish Ab peptide oligomer binding by NLGN1 and NRXN2a (17).…”

mentioning

confidence: 99%

Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer's disease

et al. 2018

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Interactions of the presynaptic proteins, neuronal pentraxin 2 (NPTX2) and neurexin 2a (NRXN2a), with their respective postsynaptic functional partners, GluA4-containing glutamate (AMPA4) receptor and neuroligin 1 (NLGN1), enhance excitatory synaptic activity in some areas of the hippocampus and cerebral cortex. As early damage of such excitatory circuits in the brain tissues of participants with Alzheimer's disease (AD) correlates with cognitive losses, plasma neuron-derived exosome (NDE) levels of these 2 pairs of specialized synaptic proteins were quantified to assess their biomarker characteristics. The NDE contents of all 4 proteins were decreased significantly in AD dementia (n = 46), and diminished levels of AMPA4 and NLGN1 correlated with the extent of cognitive loss. In a preclinical period, 6-11 yr before the onset of dementia, the NDE levels of all but NPTX2 were significantly lower than those of matched controls, and levels of all proteins declined significantly with the development of dementia. Reductions in NDE levels of these specialized excitatory synaptic proteins may therefore be indicative of the extent of cognitive loss and may reflect progression of the severity of AD.-Goetzl, E. J., Abner, E. L., Jicha, G. A., Kapogiannis, D., Schwartz, J. B. Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer's disease. FASEB J. 32, 888-893 (2018). www.fasebj.orgDiminished synaptic function and loss of synapses are characteristic early elements of the neuropathology of Alzheimer's disease (AD), usually attributed to the neuronal deposition of neurotoxic amyloid-b (Ab) peptide oligomers (1, 2). The distribution and extent of brain synaptic pathology in postmortem brain tissues of patients with AD correlate generally with the severity of premortem cognitive loss (3, 4). Our initial analyses of plasma neuron-derived exosome (NDE) content of several synaptic proteins in AD demonstrated lower levels-similar to decreases in postmortem AD brain tissues-compared with those of matched controls. In cross-sectional studies, the plasma NDE levels of the presynaptic proteins, synaptotagmin and synaptophysin, and of the postsynaptic proteins, synaptopodin and neurogranin, in patients with AD were significantly lower than those for controls, whereas plasma NDE levels of the synaptic membrane protein, GAP43, were only marginally lower in patients with AD than in controls (5). The same synaptic proteins in NDEs from the plasma of participants who were initially cognitively normal but who subsequently developed definite AD dementia were at significantly lower preclinical levels than in plasma NDEs of matched controls (5). There was also a progressive decline of plasma NDE levels of synaptotagmin, synaptopodin, and GAP43, but not of synaptophysin or neurogranin, in these participants 2-10 yr later at the time of diagnosis of AD dementia.Synaptic proteins that were investigated in our first study are widely distributed in CNS synapses and share fun...

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A truncating mutation in Alzheimer's disease inactivates neuroligin-1 synaptic function

Cited by 25 publications

References 31 publications

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer's disease

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