Subcellular proteomics of dopamine neurons in the mouse brain

Author:

Hobson Benjamin D123ORCID,Choi Se Joon4,Mosharov Eugene V4,Soni Rajesh K5ORCID,Sulzer David34678ORCID,Sims Peter A18910ORCID

Affiliation:

1. Department of Systems Biology, Columbia University Irving Medical Center

2. Medical Scientist Training Program, Columbia University Irving Medical Center

3. Department of Psychiatry, Columbia University Irving Medical Center

4. Division of Molecular Therapeutics, New York State Psychiatric Institute

5. Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center

6. Department of Neurology, Columbia University Irving Medical Center

7. Department of Pharmacology, Columbia University Irving Medical Center

8. Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network

9. Department of Biochemistry & Molecular Biophysics, Columbia University Irving Medical Center

10. Sulzberger Columbia Genome Center, Columbia University Irving Medical Center

Abstract

Dopaminergic neurons modulate neural circuits and behaviors via dopamine (DA) release from expansive, long range axonal projections. The elaborate cytoarchitecture of these neurons is embedded within complex brain tissue, making it difficult to access the neuronal proteome using conventional methods. Here, we demonstrate APEX2 proximity labeling within genetically targeted neurons in the mouse brain, enabling subcellular proteomics with cell-type specificity. By combining APEX2 biotinylation with mass spectrometry, we mapped the somatodendritic and axonal proteomes of midbrain dopaminergic neurons. Our dataset reveals the proteomic architecture underlying proteostasis, axonal metabolism, and neurotransmission in these neurons. We find that most proteins encoded by DA neuron-enriched genes are localized within striatal dopaminergic axons, including ion channels with previously undescribed axonal localization. These proteomic datasets provide a resource for neuronal cell biology, and this approach can be readily adapted for study of other neural cell types.

Funder

National Institutes of Health

Aligning Science Across Parkinson's

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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