TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis
Summary: A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass spectrometry-based proteomics to query c...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-01-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723016479 |
| _version_ | 1827389284484644864 |
|---|---|
| author | Amanda J. Guise Santosh A. Misal Richard Carson Jen-Hwa Chu Hannah Boekweg Daisha Van Der Watt Nora C. Welsh Thy Truong Yiran Liang Shanqin Xu Gina Benedetto Jake Gagnon Samuel H. Payne Edward D. Plowey Ryan T. Kelly |
| author_facet | Amanda J. Guise Santosh A. Misal Richard Carson Jen-Hwa Chu Hannah Boekweg Daisha Van Der Watt Nora C. Welsh Thy Truong Yiran Liang Shanqin Xu Gina Benedetto Jake Gagnon Samuel H. Payne Edward D. Plowey Ryan T. Kelly |
| author_sort | Amanda J. Guise |
| collection | DOAJ |
| description | Summary: A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass spectrometry-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control tissues. In a follow-up analysis, we examine the impact of stratification of MNs based on cytoplasmic transactive response DNA-binding protein 43 (TDP-43)+ inclusion pathology on the profiles of 2,238 proteins. We report extensive overlap in differentially abundant proteins identified in ALS MNs with or without overt TDP-43 pathology, suggesting early and sustained dysregulation of cellular respiration, mRNA splicing, translation, and vesicular transport in ALS. Together, these data provide insights into proteome-level changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein dynamics in human neurologic diseases. |
| first_indexed | 2024-03-08T16:32:24Z |
| format | Article |
| id | doaj.art-8a6acb1de53f412fbde8d06f4b44f6e9 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-08T16:32:24Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-8a6acb1de53f412fbde8d06f4b44f6e92024-01-06T04:38:45ZengElsevierCell Reports2211-12472024-01-01431113636TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosisAmanda J. Guise0Santosh A. Misal1Richard Carson2Jen-Hwa Chu3Hannah Boekweg4Daisha Van Der Watt5Nora C. Welsh6Thy Truong7Yiran Liang8Shanqin Xu9Gina Benedetto10Jake Gagnon11Samuel H. Payne12Edward D. Plowey13Ryan T. Kelly14Biogen, Inc., Cambridge, MA 02142, USADepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USADepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USABiogen, Inc., Cambridge, MA 02142, USABiology Department, Brigham Young University, Provo, UT 84602, USABiology Department, Brigham Young University, Provo, UT 84602, USABiogen, Inc., Cambridge, MA 02142, USADepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USADepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USABiogen, Inc., Cambridge, MA 02142, USABiogen, Inc., Cambridge, MA 02142, USABiogen, Inc., Cambridge, MA 02142, USABiology Department, Brigham Young University, Provo, UT 84602, USABiogen, Inc., Cambridge, MA 02142, USA; Corresponding authorDepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA; Corresponding authorSummary: A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass spectrometry-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control tissues. In a follow-up analysis, we examine the impact of stratification of MNs based on cytoplasmic transactive response DNA-binding protein 43 (TDP-43)+ inclusion pathology on the profiles of 2,238 proteins. We report extensive overlap in differentially abundant proteins identified in ALS MNs with or without overt TDP-43 pathology, suggesting early and sustained dysregulation of cellular respiration, mRNA splicing, translation, and vesicular transport in ALS. Together, these data provide insights into proteome-level changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein dynamics in human neurologic diseases.http://www.sciencedirect.com/science/article/pii/S2211124723016479CP: NeuroscienceCP: Molecular biology |
| spellingShingle | Amanda J. Guise Santosh A. Misal Richard Carson Jen-Hwa Chu Hannah Boekweg Daisha Van Der Watt Nora C. Welsh Thy Truong Yiran Liang Shanqin Xu Gina Benedetto Jake Gagnon Samuel H. Payne Edward D. Plowey Ryan T. Kelly TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis Cell Reports CP: Neuroscience CP: Molecular biology |
| title | TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis |
| title_full | TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis |
| title_fullStr | TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis |
| title_full_unstemmed | TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis |
| title_short | TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis |
| title_sort | tdp 43 stratified single cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis |
| topic | CP: Neuroscience CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723016479 |
| work_keys_str_mv | AT amandajguise tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT santoshamisal tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT richardcarson tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT jenhwachu tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT hannahboekweg tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT daishavanderwatt tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT noracwelsh tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT thytruong tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT yiranliang tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT shanqinxu tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT ginabenedetto tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT jakegagnon tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT samuelhpayne tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT edwarddplowey tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis AT ryantkelly tdp43stratifiedsinglecellproteomicsofpostmortemhumanspinalmotorneuronsrevealsproteindynamicsinamyotrophiclateralsclerosis |