A Subtype of Dopamine Neurons is Vulnerable to Neurodegeneration in Parkinson’s Disease
Post by Shireen Parimoo
The takeaway
Parkinson’s disease is characterized by the loss of dopamine (DA) neurons, with some DA neurons more vulnerable than others. One subtype of DA neurons that strongly express genes that have previously been linked to Parkinson’s disease is most susceptible to degeneration.
What's the science?
Parkinson’s disease (PD) is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc). However, neuronal degeneration is not uniform across all subtypes of DA neurons, as some survive late into disease progression while others die early on. The genetic and molecular characteristics of the different DA neuron subtypes that make them selectively vulnerable to PD-related degeneration are not currently known. This week in Nature Neuroscience, Kamath and colleagues performed molecular profiling of DA neurons in the SNpc to identify the subtypes most at risk for degeneration in PD.
How did they do it?
The authors first identified DA and non-DA cells in post-mortem human midbrain slices, as well as the rodent and macaque midbrain, using single-nucleus RNA sequencing. They performed a clustering analysis and compared the presence of certain genes against an existing database to identify different cell types within the midbrain tissue. Within the DA neurons, they quantified the presence of certain molecular biomarkers, such as transcription factors and regulons (set of genes whose expression is controlled by a common regulatory region), to further distinguish between the different DA neuron subtypes. Next, they spatially localized the DA neuron subtypes within the macaque SNpc using Slide-seq (a spatial phenotyping technique) and in the human SNpc using fluorescence imaging. To determine which DA neuron subtypes were more vulnerable to degeneration, the authors compared post-mortem tissue of PD patients and controls. Lastly, they examined the presence of genetic and molecular markers associated with familial and sporadic PD in the different DA neuron subtypes.
What did they find?
Midbrain cells were grouped into seven categories (e.g., astrocytes, DA neurons, microglia, etc.), within which DA neurons were differentiated from non-DA neurons based on the presence of the Nr4a2 gene. There were two broad classes of DA neurons in the human and macaque midbrains: those that strongly expressed the SOX6 genes and those that strongly expressed the CALB1 genes. The SOX6-expressing neurons – particularly the subtype containing the AGTR1 gene – were primarily localized to the ventral SNpc while the CALB1-expressing neurons were predominantly in the dorsal SNpc. Within the DA neuron subtypes, there was considerable heterogeneity in the expression of transcription factors and regulon activity. This means that different subtypes of DA neurons in both the human and macaque midbrain can be distinguished from one another based on the expression of specific transcription factors.
In PD, SOX6-expressing DA neurons in the ventral SNpc were more vulnerable to neurodegeneration, especially the AGTR1 subtype, compared to CALB1-expressing neurons in the dorsal SNpc. Moreover, the AGTR1 subtype was strongly enriched for genes previously linked to PD by genome-wide association studies. Additionally, this subtype was found to have upregulated genes linked to neurodegeneration in mouse models of PD, which explains their selective vulnerability to PD-related degeneration. Together, these results implicate the SOX-AGTR1 subtype of DA neurons in PD due to the marked presence of genetic markers associated with neurodegeneration.
What's the impact?
The authors profiled DA neurons in the midbrain using single-nucleus RNA-sequencing, which allowed the authors to identify and spatially localize the DA neurons within the substantia nigra pars compacta that are selectively vulnerable to PD-related degeneration. These findings not only strengthen our understanding of the biomarkers associated with PD, but the identification of transcription factors that drive neurodegeneration in PD can additionally inform efforts to develop targeted treatments and therapies.