# Don’t die like me: Which proteins are responsible for the selective neuronal vulnerability within the substantia nigra?

## TL;DR

This study identifies proteins that may explain why some neurons in the substantia nigra are more vulnerable to degeneration in Parkinson's disease.

## Contribution

The study reveals specific proteins linked to selective neuronal vulnerability in the substantia nigra using donor-specific proteomic analysis.

## Key findings

- Nine proteins were found to be differentially regulated between ventral and dorsal tiers of the substantia nigra.
- Differentially regulated proteins are associated with cytoskeleton, neuronal plasticity, and calcium homeostasis.
- Seven proteins were more abundant in the dorsal tier, while two were more abundant in the ventral tier.

## Abstract

A hallmark of Parkinson’s disease is the specific degeneration of dopaminergic neurons in the substantia nigra pars compacta. Interestingly, not all of these neurons are affected to the same extent. Studies revealed that neurons located more ventrally within the substantia nigra pars compacta have a higher prevalence to degenerate than those located in the dorsal tier. The underlying reasons for this selective neuronal vulnerability are still unknown. The aim of the present study was to gain a better understanding of molecular differences between these two neuronal subpopulations that may explain the selective neuronal vulnerability within the human substantia nigra. For this purpose, the neurons from the ventral as well as dorsal tier of the substantia nigra were specifically isolated out of neuropathologically unremarkable human substantia nigra sections with laser microdissection. Following, their proteome was analyzed by data independent acquisition mass spectrometry. The samples were analysed donor-specifically and not pooled for this purpose. A total of 5,391 proteins were identified in the substantia nigra. Of these, 2,453 proteins could be quantified in 100% of the dorsal tier samples. 1,629 could be quantified in 100% of the ventral tier samples. Nine proteins were differentially regulated with a log2 value ≥0.5 and a Qvalue ≤0.05. Of these 7 were higher abundant in the dorsal tier and 2 higher in the ventral tier. These proteins are associated with the cytoskeleton, neuronal plasticity, or calcium homeostasis. With these findings a deeper understanding can be gained of the selective neuronal vulnerability within the substantia nigra and of protective mechanisms against neurodegeneration in specific neuronal subpopulations.