Cell Rep. 2024 Jan 05. pii: S2211-1247(23)01647-9. [Epub ahead of print]43(1): 113636
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.
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.
Keywords: ALS; CP: Molecular biology; CP: Neuroscience; STMN2; TDP-43 proteinopathy; laser capture; motor neuron; nanoPOTS; retromer; single-cell proteomics