Researchers discover a select group of neurons in the substantia nigra that enhances heritable risk of Parkinson’s disease

Research Source: Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, Cambridge, MA, USA

Summary: The molecular features of dopaminergic neurons susceptible to degradation have long been elusive and now a sub-set of neurons in the substantia nigra expressing the gene AGTR1 have been identified and shown to be vulnerable to cell-intrinsic processes that lead to their demise.

By Robert G. Jesky, MMed., PhD

FULL STORY

A group of researchers out of the Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research have revealed molecular mechanisms of why certain neurons in a region of the brain called the substantia nigra pars compacta (SNpc) degenerate while others survive even into the late stages of Parkinson’s disease (PD).

Dissection of single-cell gene expression profiles has proven challenging, however a novel tool called single-cell RNA-sequencing technology (scRNA-seq) is now advancing our understanding of specific neuronal cell-type abnormalities found in various neurological conditions. Use of this technology to examine post-mortem human brains offers a unique window into the distinct changes single cells undergo in disease states. Employing scRNA-seq, Kamath and Abdulraouf, the lead authors of the study, and others found that different populations of dopaminergic (DA) neurons have distinct molecular signatures, suggesting that they have different developmental fates. Furthermore, they showed that different populations of DA neurons have different patterns of gene expression, with a subset localized to the ventral region of the substantia nigra that express Angiotensin II Receptor Type 1 (AGTR1) found to be those most commonly associated with neuron loss in Parkinson’s disease.

Neurons require constant communication with neighboring cells and do so through a process called neurotransmission. Errors in neurotransmission can lead to deleterious changes in cellular function which implicates other neuronal subtypes in disease pathogenesis. To evaluate the potential of other DA cell-types that may be involved in disease development they looked at transcriptionally distinct markers and discovered four cellular clusters that uniquely expressed the SRY-Box transcription factor 6 (SOX6).

Neuroscience for Beginners: Transcription factors are proteins that turn genes “on” or “off” by binding to upstream regulatory elements of genes that in turn dictate cell fate and determine intrinsic cellular processes. SOX6 is an extremely versatile transcription factor shown to be highly important for cell type specification in the brain where it regulates cortical interneuron differentiation and progenitor cells (a type of cell that will differentiate into a specific “target” cell). Basically, transcription factors have the capacity to program cells in a fashion such that their instructions are the blueprint that tells a cell what type it should become, and what role it’s to play in a cellular cluster.

Taking their work one step further with a focus on ruling out intrinsic bias in sampling and identifying true underlying biological states, the authors looked to corroborate their findings with those found in other species. Implementing the use of a high through-put profiling method to evaluate if the DA neuronal subtypes in the SNpc were evolutionarily conserved, Kamath and others conducted a comparative analysis across 4 species. Perhaps not surprisingly, they found that in nine of our ten populations the DA neurons shared considerable homology. However, they identified one molecularly distinct subset of cells in the dorsal tier in macaque monkeys and humans co-labelled with calbindin 1 and a guanosine triphosphate (GTP)-binding protein dubbed CALB1_GEM. This is a key finding in relation to expanding our understanding of molecular determinants in the susceptibility of distinct cell populations in disease development, especially as SOX6-positive neuronal populations conversely show increased vulnerability in PD.  

Demarcation of dorsal and ventral tiers in the midbrain has been shown to coincide with preferential distribution of molecularly distinct cell types with SOX6_AGTR1 populations in the ventral tier and CALB1_GEM enriched in the dorsal tier. Sure enough, the results showed that in accordance with cell type distribution there was a marked loss of SOX6_AGTR1 DA neurons, and a comparative increase in CALB1_GEM clusters. Such findings are congruent with other studies showing that the ventral tier is predisposed to atypical degeneration, and thus increased vulnerability in PD.

Such a relatively clear demarcation of PD-associated neurodegenerative susceptibility in the ventral midbrain, may lead one to ask why. The study’s researchers sought to answer this by cross-referencing a list of genes known to confer enhanced PD risk against the eight major neuronal types in the SNpc, and found that only the DA neurons expressed familial gene variants. Doubling down on ensuring the validity of their findings, the researchers used a binate statistical approach to contrast the genetic risk genes against DA cell types and found that the increased risk was predominately associated with the molecular distinct SOX6_AGTR1 subtype.

As the authors note, “the partitioning of heritable disease risk preferentially to the most vulnerable DA population (i.e., SOX6_AGTR1) provides evidence that the genetic influences of PD-associated degeneration are largely cell intrinsic”. This is further supported by the findings that the most vulnerable neurons harboring risk variants are also those subject to transcriptional changes involved in the regulation of canonical cell stress pathways, namely those encoded by two genes: Tumor Protein P53 (TP53) and Nuclear Receptor Subfamily 2 Group F Member 2 (NR2F2), both of which are cardinal to nervous system development.

Collectively, this study elucidates that a substantial fraction of PD risk is mediated by genes that act in specific neurons to promote neurodegeneration. Having advanced our understanding of specific molecular determinates in vulnerable DA neurons, the authors have opened up an important avenue for therapeutic innovation and better diagnostic biomarkers.

Journal Reference:

Kamath, T., Abdulraouf, A., Burris, S.J. et al. Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease. Nat Neurosci 25, 588–595 (2022). https://doi.org/10.1038/s41593-022-01061-1

Cite This Page:

APA Jesky, R. (2022, July 11). Researchers discover a select group of neurons in the substantia nigra that enhances the heritable risk of Parkinson’s disease. NeuroSavi