The Putative Drosophila TMEM184B Ortholog Tmep Ensures Proper Locomotion by Restraining Ectopic Firing at the Neuromuscular Junction

Cho, Tiffany S.; Beigaitė, Eglė; Klein, Nathaniel; Sweeney, Sean T.; Bhattacharya, Martha R.C.

doi:10.1007/s12035-022-02760-3

Cited by 3 publications

(11 citation statements)

References 64 publications

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“…The most differentially expressed GO Biological Processes associated with synapses were in synaptic transmission and plasticity. This prediction is consistent with existing data showing that Tmem184b mutation causes hyperexcitability at glutamatergic synapses in Drosophila [9].…”

Section: Synaptic Protein-protein Interaction Network and Biological ...supporting

confidence: 93%

“…TMEM184B expression is required for maintenance of synaptic structure at neuromuscular junctions in both mouse and fly [11, 9]. We wondered if this role would extend to the hippocampus, a center for learning and memory processing.…”

Section: Resultsmentioning

confidence: 99%

“…This upregulation of mRNA could reflect a compensation for presynaptic dysfunction, an inappropriate dendritic overgrowth, or a failure to prune exuberant synapses. In fly models of mutation of the TMEM184B ortholog, Tmep , extra active zones and synaptic release sites (boutons) are observed at neuromuscular junctions [9], suggesting that additional synapses may be a common effect of TMEM184B disruption. Further detailed analysis of hippocampal synaptic morphology and physiology will be necessary to parse apart these possibilities.…”

Section: Discussionmentioning

confidence: 99%

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Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus

Larsen¹,

Wright²,

Hart³

et al. 2022

Preprint

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In Alzheimer’s Disease (AD) and other dementias, hippocampal synaptic dysfunction and loss contribute to the progression of memory impairment. Recent analysis of human AD transcriptomes has provided a list of gene candidates that may serve as drivers of disease. One such candidate is the membrane protein TMEM184B. To evaluate whether TMEM184B contributes to neurological impairment, we asked whether loss of TMEM184B in mice causes gene expression or behavior alterations, focusing on the hippocampus. Because one major risk factor for AD is age, we compared young adult (5-month-old) and aged (15-month-old) wild type and Tmem184b-mutant mice to assess the dual contributions of age and genotype. TMEM184B loss altered expression of pre- and post-synaptic transcripts by 5 months and continued through 15 months, specifically affecting genes involved in synapse assembly and neural development. Wnt-activated enhancer elements were enriched among differentially expressed genes, suggesting an intersection with this pathway. Few differences existed between young adult and aged mutants, suggesting that transcriptional effects of TMEM184B loss are relatively constant. To understand how TMEM184B disruption may impact behaviors, we evaluated memory using the novel object recognition test and anxiety using the elevated plus maze. Young adult Tmem184b-mutant mice show normal object discrimination, suggesting a lack of memory impairment at this age. However, mutant mice showed decreased anxiety, a phenotype seen in neurodevelopmental disorders. Taken together, our data suggest that TMEM184B is required for proper synaptic gene expression and function but may not be causal for AD and related dementias.

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Section: Synaptic Protein-protein Interaction Network and Biological ...supporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus

Larsen¹,

Wright²,

Hart³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…TMEM184B expression is required for maintenance of synaptic structure at neuromuscular junctions in both mouse and fly [ 9 , 11 ]. We wondered if this role would extend to the hippocampus, a center for learning and memory processing.…”

Section: Resultsmentioning

confidence: 99%

“…Through recent RNAseq analyses, the transmembrane protein TMEM184B was predicted as a candidate protein that could promote AD progression [ 8 ]. TMEM184B is a 7-pass transmembrane protein expressed broadly in the nervous system and is thought to play a role in neuronal excitability, synaptic structure, and expression of key developmental and adult pathways involved in neuronal differentiation [ 9 , 10 ]. Using analysis of the ROSMAP and MAYO clinic human cohorts, TMEM184B was predicted to drive AD-associated gene expression patterns in the dorsolateral prefrontal cortex and temporal cortex, respectively [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus

Wright,

Larsen,

Coloma-Roessle

et al. 2023

BMC Genomics

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In Alzheimer’s Disease (AD) and other dementias, hippocampal synaptic dysfunction and loss contribute to the progression of memory impairment. Recent analysis of human AD transcriptomes has provided a list of gene candidates that may serve as drivers of disease. One such candidate is the membrane protein TMEM184B. To evaluate whether TMEM184B contributes to neurological impairment, we asked whether loss of TMEM184B in mice causes gene expression or behavior alterations, focusing on the hippocampus. Because one major risk factor for AD is age, we compared young adult (5-month-old) and aged (15-month-old) wild type and Tmem184b-mutant mice to assess the dual contributions of age and genotype. TMEM184B loss altered expression of pre- and post-synaptic transcripts by 5 months and continued through 15 months, specifically affecting genes involved in synapse assembly and neural development. Wnt-activated enhancer elements were enriched among differentially expressed genes, suggesting an intersection with this pathway. Few differences existed between young adult and aged mutants, suggesting that transcriptional effects of TMEM184B loss are relatively constant. To understand how TMEM184B disruption may impact behaviors, we evaluated memory using the novel object recognition test and anxiety using the elevated plus maze. Young adult Tmem184b-mutant mice show normal object discrimination, suggesting a lack of memory impairment at this age. However, mutant mice showed decreased anxiety, a phenotype seen in some neurodevelopmental disorders. Taken together, our data suggest that TMEM184B is required for proper synaptic gene expression and anxiety-related behavior and is more likely to be linked to neurodevelopmental disorders than to dementia.

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Pathogenic variants inTMEM184Bcause a neurodevelopmental syndrome via alteration of metabolic signaling

Chapman,

Ullah,

Yahiku

et al. 2024

Preprint

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Transmembrane protein 184B (TMEM184B) is an endosomal 7-pass transmembrane protein with evolutionarily conserved roles in synaptic structure and axon degeneration. We report six pediatric patients who havede novoheterozygous variants inTMEM184B. All individuals harbor rare missense or mRNA splicing changes and have neurodevelopmental deficits including intellectual disability, corpus callosum hypoplasia, seizures, and/or microcephaly. TMEM184B is predicted to contain a pore domain, wherein many human disease-associated variants cluster. Structural modeling suggests that all missense variants alter TMEM184B protein stability. To understand the contribution of TMEM184B to neural developmentin vivo, we suppressed the TMEM184B ortholog in zebrafish and observed microcephaly and reduced anterior commissural neurons, aligning with patient symptoms. EctopicTMEM184Bexpression resulted in dominant effects for K184E and G162R. However,in vivocomplementation studies demonstrate that all other variants tested result in diminished protein function and indicate a haploinsufficiency basis for disease. Expression of K184E and other variants increased apoptosis in cell lines and altered nuclear localization of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, suggesting disrupted nutrient signaling pathways. Together, our data indicate that TMEM184B variants cause cellular metabolic disruption likely through divergent molecular effects that all result in abnormal neural development.

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The Putative Drosophila TMEM184B Ortholog Tmep Ensures Proper Locomotion by Restraining Ectopic Firing at the Neuromuscular Junction

Cited by 3 publications

References 64 publications

Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus

Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus

Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus

Pathogenic variants inTMEM184Bcause a neurodevelopmental syndrome via alteration of metabolic signaling

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