Slitrk missense mutations associated with neuropsychiatric disorders distinctively impair Slitrk trafficking and synapse formation
Slitrks are a six-member family of synapse organizers that control excitatory and inhibitory synapse formation by forming trans-synaptic adhesions with LAR receptor protein tyrosine phosphatases (PTPs). Intriguingly, genetic mutations of Slitrks have been associated with a multitude of neuropsychiat...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-10-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnmol.2016.00104/full |
| _version_ | 1818614033747542016 |
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| author | Hyeyeon Kang Kyung Ah Han Seong Youn Won Ho Min Kim Young-Ho Lee Jaewon Ko JI WON UM |
| author_facet | Hyeyeon Kang Kyung Ah Han Seong Youn Won Ho Min Kim Young-Ho Lee Jaewon Ko JI WON UM |
| author_sort | Hyeyeon Kang |
| collection | DOAJ |
| description | Slitrks are a six-member family of synapse organizers that control excitatory and inhibitory synapse formation by forming trans-synaptic adhesions with LAR receptor protein tyrosine phosphatases (PTPs). Intriguingly, genetic mutations of Slitrks have been associated with a multitude of neuropsychiatric disorders. However, nothing is known about the neuronal and synaptic consequences of these mutations. Here, we report the structural and functional effects on synapses of various rare de novo mutations identified in patients with schizophrenia or Tourette syndrome. A number of single amino acid substitutions in Slitrk1 (N400I or T418S) or Slitrk4 (V206I or I578V) reduced their surface expression levels. These substitutions impaired glycosylation of Slitrks expressed in HEK293T cells, caused retention of Slitrks in the endoplasmic reticulum and cis-Golgi compartment in COS-7 cells and neurons, and abolished Slitrk binding to PTPδ. Furthermore, these substitutions eliminated the synapse-inducing activity of Slitrks, abolishing their functional effects on synapse density in cultured neurons. Strikingly, a valine-to-methionine mutation in Slitrk2 (V89M) compromised synapse formation activity in cultured neuron, without affecting surface transport, expression, or synapse-inducing activity in coculture assays. Similar deleterious effects were observed upon introduction of the corresponding valine-to-methionine mutation into Slitrk1 (V85M), suggesting that this conserved valine residue plays a key role in maintaining the synaptic functions of Slitrks. Collectively, these data indicate that inactivation of distinct cellular mechanisms caused by specific Slitrk dysfunctions may underlie Slitrk-associated neuropsychiatric disorders in humans, and provide a robust cellular readout for the development of knowledge-based therapies. |
| first_indexed | 2024-12-16T16:11:35Z |
| format | Article |
| id | doaj.art-dda807528cc54ca89ef456d472f93dae |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-16T16:11:35Z |
| publishDate | 2016-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-dda807528cc54ca89ef456d472f93dae2022-12-21T22:25:12ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992016-10-01910.3389/fnmol.2016.00104216323Slitrk missense mutations associated with neuropsychiatric disorders distinctively impair Slitrk trafficking and synapse formationHyeyeon Kang0Kyung Ah Han1Seong Youn Won2Ho Min Kim3Young-Ho Lee4Jaewon Ko5JI WON UM6Yonsei University College of MedicineYonsei University College of MedicineKAISTKAISTYonsei University College of MedicineYonsei UniversityYonsei University College of MedicineSlitrks are a six-member family of synapse organizers that control excitatory and inhibitory synapse formation by forming trans-synaptic adhesions with LAR receptor protein tyrosine phosphatases (PTPs). Intriguingly, genetic mutations of Slitrks have been associated with a multitude of neuropsychiatric disorders. However, nothing is known about the neuronal and synaptic consequences of these mutations. Here, we report the structural and functional effects on synapses of various rare de novo mutations identified in patients with schizophrenia or Tourette syndrome. A number of single amino acid substitutions in Slitrk1 (N400I or T418S) or Slitrk4 (V206I or I578V) reduced their surface expression levels. These substitutions impaired glycosylation of Slitrks expressed in HEK293T cells, caused retention of Slitrks in the endoplasmic reticulum and cis-Golgi compartment in COS-7 cells and neurons, and abolished Slitrk binding to PTPδ. Furthermore, these substitutions eliminated the synapse-inducing activity of Slitrks, abolishing their functional effects on synapse density in cultured neurons. Strikingly, a valine-to-methionine mutation in Slitrk2 (V89M) compromised synapse formation activity in cultured neuron, without affecting surface transport, expression, or synapse-inducing activity in coculture assays. Similar deleterious effects were observed upon introduction of the corresponding valine-to-methionine mutation into Slitrk1 (V85M), suggesting that this conserved valine residue plays a key role in maintaining the synaptic functions of Slitrks. Collectively, these data indicate that inactivation of distinct cellular mechanisms caused by specific Slitrk dysfunctions may underlie Slitrk-associated neuropsychiatric disorders in humans, and provide a robust cellular readout for the development of knowledge-based therapies.http://journal.frontiersin.org/Journal/10.3389/fnmol.2016.00104/fullSchizophreniasynapse formationTourette’s Syndrometransmembrane proteinSlitrks |
| spellingShingle | Hyeyeon Kang Kyung Ah Han Seong Youn Won Ho Min Kim Young-Ho Lee Jaewon Ko JI WON UM Slitrk missense mutations associated with neuropsychiatric disorders distinctively impair Slitrk trafficking and synapse formation Frontiers in Molecular Neuroscience Schizophrenia synapse formation Tourette’s Syndrome transmembrane protein Slitrks |
| title | Slitrk missense mutations associated with neuropsychiatric disorders distinctively impair Slitrk trafficking and synapse formation |
| title_full | Slitrk missense mutations associated with neuropsychiatric disorders distinctively impair Slitrk trafficking and synapse formation |
| title_fullStr | Slitrk missense mutations associated with neuropsychiatric disorders distinctively impair Slitrk trafficking and synapse formation |
| title_full_unstemmed | Slitrk missense mutations associated with neuropsychiatric disorders distinctively impair Slitrk trafficking and synapse formation |
| title_short | Slitrk missense mutations associated with neuropsychiatric disorders distinctively impair Slitrk trafficking and synapse formation |
| title_sort | slitrk missense mutations associated with neuropsychiatric disorders distinctively impair slitrk trafficking and synapse formation |
| topic | Schizophrenia synapse formation Tourette’s Syndrome transmembrane protein Slitrks |
| url | http://journal.frontiersin.org/Journal/10.3389/fnmol.2016.00104/full |
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