Niu M, Cao W, Wang Y, Zhu Q, Luo J, Wang B, Zheng H, Weitz DA, Zong C.
Droplet-based transcriptome profiling of individual synapses.
Nat Biotechnol. 2023 Jan 16;
PubMed.
The approach is interesting and may provide insights into synaptosome characteristics that reflect synaptic function. Many mRNAs translated in the synaptic spine, such as neurotransmitter receptors, are important for post-synaptic function and regulation. This technology may help us better understand diversity of synapses in the brain in health, and how they change in disease.
As opposed to the currently available bulk-sequencing approaches, this MATQ-Drop method allows for profiling of the transcriptome at individual synapses. There are various types of synapses in the brain and, importantly, they are differently affected in neurodegenerative disorders. This new method may now allow us to discover synapse-type-specific changes in the local transcriptome in Alzheimer’s disease.
The strength of this method lies in the combination of single-synapse sequencing with single-nuclei sequencing, as the authors have done here. Additionally, because the method allows comparison of mature and nascent RNA, it will be useful to the elucidate how the local splicing landscape in individual synapse types is altered in conditions such as AD.
The paper is data-rich and provides several intriguing starting points for future research. For example, in AD, expression of three complement component genes were significantly changed in synapses, but not in nuclei, indicating that their transport and recruitment to synapses is upregulated. It will be interesting to find out what processes control the post-transcriptional regulation of these genes in the context of neurodegeneration. More generally, the data presented in his study emphasize the importance of changes to local translation in AD pathogenesis.
I am very impressed with this new methodology for examining gene-expression changes at the synaptic level. This is a very clever technique and it does appear to get past some issues with transcriptomic analysis, including single-nucleus RNA-Seq, which could easily miss the synapses present on neurites.
I am not surprised to see both C3 and C1q involvement in the microglial synaptome. Both play a role in microglial-mediated synaptic pruning, as Beth Stevens, Dori Schaefer, Andrea Tenner, Susana Rosi, and my labs have demonstrated in the past. Overall, this looks like a big step forward in CNS transcriptomics, especially since synapses are so relevant to neurological aging and disease. I hope it will be available to the field at large in the near future.
In this study, the authors have combined MATQ-Seq, a highly sensitive quantitative single-cell RNA-Seq technology they have developed, with droplet technology to enable quantitative RNA-Seq at high resolution. By using MATQ-Drop, they were able to analyze synaptosomes, which are enriched in RNAs distinct from those in the cytoplasm, at the single-compartment level. The authors successfully detected transcriptome differences at the synaptic level in mice, humans, and in a mouse model of Alzheimer's disease.
This is a very important technique and has clarified RNA abnormalities in the specialized compartment of the synapse. This technique is also interesting because it has the potential to detect transcriptome abnormalities in various compartments and organelles in the cell if their biochemical isolation is possible. For example, it has the potential to reveal new "intracellular transcriptome diversity" in the cytoplasm, which was believed to be a single environment before the biology of by liquid-liquid phase separation was discovered.
The finding, in mice, of neuron-oligodendrocyte junctions might be further interesting because, in addition to microglia, oligodendrocyte precursor cells (OPCs) prune synapses in the mouse visual cortex (Auguste et al., 2022).
References:
Auguste YS, Ferro A, Kahng JA, Xavier AM, Dixon JR, Vrudhula U, Nichitiu AS, Rosado D, Wee TL, Pedmale UV, Cheadle L.
Oligodendrocyte precursor cells engulf synapses during circuit remodeling in mice.
Nat Neurosci. 2022 Oct;25(10):1273-1278. Epub 2022 Sep 28
PubMed.
Comments
Northwestern University Feinberg School of Medicine
The approach is interesting and may provide insights into synaptosome characteristics that reflect synaptic function. Many mRNAs translated in the synaptic spine, such as neurotransmitter receptors, are important for post-synaptic function and regulation. This technology may help us better understand diversity of synapses in the brain in health, and how they change in disease.
View all comments by Robert VassarColumbia University
As opposed to the currently available bulk-sequencing approaches, this MATQ-Drop method allows for profiling of the transcriptome at individual synapses. There are various types of synapses in the brain and, importantly, they are differently affected in neurodegenerative disorders. This new method may now allow us to discover synapse-type-specific changes in the local transcriptome in Alzheimer’s disease.
The strength of this method lies in the combination of single-synapse sequencing with single-nuclei sequencing, as the authors have done here. Additionally, because the method allows comparison of mature and nascent RNA, it will be useful to the elucidate how the local splicing landscape in individual synapse types is altered in conditions such as AD.
The paper is data-rich and provides several intriguing starting points for future research. For example, in AD, expression of three complement component genes were significantly changed in synapses, but not in nuclei, indicating that their transport and recruitment to synapses is upregulated. It will be interesting to find out what processes control the post-transcriptional regulation of these genes in the context of neurodegeneration. More generally, the data presented in his study emphasize the importance of changes to local translation in AD pathogenesis.
View all comments by Ulrich HengstAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School
I am very impressed with this new methodology for examining gene-expression changes at the synaptic level. This is a very clever technique and it does appear to get past some issues with transcriptomic analysis, including single-nucleus RNA-Seq, which could easily miss the synapses present on neurites.
I am not surprised to see both C3 and C1q involvement in the microglial synaptome. Both play a role in microglial-mediated synaptic pruning, as Beth Stevens, Dori Schaefer, Andrea Tenner, Susana Rosi, and my labs have demonstrated in the past. Overall, this looks like a big step forward in CNS transcriptomics, especially since synapses are so relevant to neurological aging and disease. I hope it will be available to the field at large in the near future.
View all comments by Cynthia LemereThe University of Tokyo
In this study, the authors have combined MATQ-Seq, a highly sensitive quantitative single-cell RNA-Seq technology they have developed, with droplet technology to enable quantitative RNA-Seq at high resolution. By using MATQ-Drop, they were able to analyze synaptosomes, which are enriched in RNAs distinct from those in the cytoplasm, at the single-compartment level. The authors successfully detected transcriptome differences at the synaptic level in mice, humans, and in a mouse model of Alzheimer's disease.
This is a very important technique and has clarified RNA abnormalities in the specialized compartment of the synapse. This technique is also interesting because it has the potential to detect transcriptome abnormalities in various compartments and organelles in the cell if their biochemical isolation is possible. For example, it has the potential to reveal new "intracellular transcriptome diversity" in the cytoplasm, which was believed to be a single environment before the biology of by liquid-liquid phase separation was discovered.
View all comments by Taisuke TomitaThe finding, in mice, of neuron-oligodendrocyte junctions might be further interesting because, in addition to microglia, oligodendrocyte precursor cells (OPCs) prune synapses in the mouse visual cortex (Auguste et al., 2022).
References:
Auguste YS, Ferro A, Kahng JA, Xavier AM, Dixon JR, Vrudhula U, Nichitiu AS, Rosado D, Wee TL, Pedmale UV, Cheadle L. Oligodendrocyte precursor cells engulf synapses during circuit remodeling in mice. Nat Neurosci. 2022 Oct;25(10):1273-1278. Epub 2022 Sep 28 PubMed.
View all comments by Charles StromeyerMake a Comment
To make a comment you must login or register.