A primate nigrostriatal atlas of neuronal vulnerability and resilience in a model of Parkinson’s disease

Abstract

The degenerative process in Parkinson’s disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. Here we generated high-quality profiles for 250,173 cells from the substantia nigra (SN) and putamen (PT) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian macaques and matched controls. Our primate model of parkinsonism recapitulates important pathologic features in nature PD and provides an unbiased view of the axis of neuronal vulnerability and resistance. We identified seven molecularly defined subtypes of nigral DaNs which manifested a gradient of vulnerability and were confirmed by fluorescence-activated nuclei sorting. Neuronal resilience was associated with a FOXP2-centered regulatory pathway shared between PD-resistant DaNs and glutamatergic excitatory neurons, as well as between humans and nonhuman primates. We also discovered activation of immune response common to glial cells of SN and PT, indicating concurrently activated pathways in the nigrostriatal system. Our study provides a unique resource to understand the mechanistic connections between neuronal susceptibility and PD pathophysiology, and to facilitate future biomarker discovery and targeted cell therapy.

Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson's disease

“…This suggests that our taxonomic scheme is impervious to the context of a mild perturbation such as LRRK2 G2019S , suggesting that our clusters are reflective of cell types, rather than cell states. It is likely, that with more severe perturbations, such as a toxin lesion, more substantial alterations of taxonomic schemes are observed 86 , 92 . However, we expect that for mild insults, day to day behavioral changes, or pharmacological paradigms, our clusters will be resistant to changes, although individual genes may vary.…”

Single-cell sequencing of the substantia nigra reveals microglial activation in a model of MPTP

“…N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a lipophilic prototoxin commonly used to induce PD models in rodents and primates ( Tang et al, 2023 ). MPTP can cross the blood–brain barrier and be oxidized to 1-methyl-4-phenylpyridinium (MPP) by monoamine oxidase B, and then MPP is concentrated in the dopaminergic terminals and cell bodies by the dopamine uptake transporter to produce toxicity ( Jackson-Lewis and Przedborski, 2007 ).…”

Table_4.XLSX

“…N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a lipophilic prototoxin commonly used to induce PD models in rodents and primates (Tang et al, 2023). MPTP can cross the blood-brain barrier and be oxidized to 1-methyl-4-phenylpyridinium (MPP) by monoamine oxidase B, and then MPP is concentrated in the dopaminergic terminals and cell bodies by the dopamine uptake transporter to produce toxicity (Jackson-Lewis and Przedborski, 2007).…”