Lower RIT2 gene activity implicated in Parkinson’s development
Study measured gene activity in more than 300,000 individual brain cells
Reduced activity of the RIT2 gene in a subtype of nerve cells — regardless of whether they produce dopamine — may be implicated in the development of Parkinson’s disease, according to a study that measured gene activity in more than 300,000 individual brain cells.
The protein encoded by RIT2 has been shown to help clear cells of toxic forms of the alpha-synuclein protein, which is thought to contribute to the loss of nerve cells in Parkinson’s.
Researchers also found various other brain cell types associated with a vulnerability to the neurodegenerative disorder, data showed.
“Our study shows the landscape of transcriptomic [gene activity] signatures with cell type resolution in a brain region that is vulnerable in Parkinson’s disease,” study co-lead Zhenyu Yue, PhD, at the Icahn School of Medicine at Mount Sinai, in New York, said in a press release. “We are surprised by a finding of a neuron type with vulnerability in [Parkinson’s disease], which has never been characterized previously.”
The study, “Molecular profiling of human substantia nigra identifies diverse neuron types associated with vulnerability in Parkinson’s disease,” was published in the journal Science Advances.
A hallmark feature of Parkinson’s is the degeneration of dopaminergic neurons — the nerve cells in the brain that produce the signaling molecule dopamine — in a region called the substantia nigra.
However, the underlying molecular mechanisms explaining why these dopaminergic neurons are susceptible to degeneration are still unknown. Moreover, whether other cell types within the substantia nigra show vulnerability in Parkinson’s needs more examination.
To address these gaps, a team led by scientists at Mount Sinai measured the gene activity of more than 300,000 individual cells in the substantia nigra from people with and without Parkinson’s.
RIT2 gene identified as a marker
Among the neurons, comprising about 13% of the nine cell types detected, the team identified three subtypes, one of which had significantly fewer cells in Parkinson’s samples than controls. They noticed that RIT2 was a marker gene for these cells, which has been associated with a susceptibility to Parkinson’s in large-scale genomic studies.
When examined more closely, the distribution of RIT2-positive neurons resembled those that tested positive for tyrosine hydroxylase (TH), a marker for dopaminergic neurons. Still, although about 30% of these cells tested negative for TH, there were fewer RIT2-positive neurons, with or without TH, in Parkinson’s samples than in controls.
In other words, RIT2-positive neurons degenerate in Parkinson’s, whether or not they produce dopamine. The findings were confirmed using midbrain organoids, which are simplified, three-dimensional versions of the brain derived from human stem cells.
Of the other two neuron clusters, researchers detected two subtypes of dopaminergic neurons associated with Parkinson’s vulnerability, a finding also confirmed in organoids.
Assessing differentially expressed genes
Next, differences in gene activity between Parkinson’s and control samples, called differentially expressed genes (DEGs), were assessed from each cell type within the substantia nigra. RIT2-positive/TH-negative neurons had the highest number of DEGs, with significantly less activity of genes that encode proteins in synapses, the gaps that nerve cells use to communicate.
Increased DEGs in Parkinson’s samples included those involved in protein production, detoxication and cellular protection, stress responses, and immunosuppression.
Differentially expressed genes then were assessed in early- and late-stage Parkinson’s samples to investigate gene activity changes during disease progression. In non-neuron cells and a small set of neurons, the stress response was activated early. In neurons that produce dopamine, the growth of new dopaminergic neurons and synaptic function were disrupted at the early stage and then suppressed over time. In the late stages, immune pathways were disrupted.
“Our study provides the opportunity to interrogate the remaining dopamine neurons at advanced disease stages and identify clues for how they are adapted and survive, while the vast majority of dopamine neurons are lost,” Yue noted.
Researchers also confirmed the altered activity of numerous genes associated with Parkinson’s, including SNCA, which encodes for alpha-synuclein, and LRRK2, for which mutants are the most common genetic cause of Parkinson’s. Notably, there was significantly less activity of the RIT2 gene in neurons.
Overall, the data showed a high degree of variability of activity among Parkinson’s-linked genes across different cell types in the substantia nigra, “suggesting the complexity of pathogenic [disease-causing] mechanisms of [Parkinson’s disease],” the researchers wrote. They also showed that multiple signaling pathways are altered in Parkinson’s.
‘Profound insights’ into Parkinson’s development
Study co-lead Bin Zhang, PhD, added, “Equally significant is the identification of molecular alterations in different brain cell types in [Parkinson’s disease]. These findings provide not only profound insights into the underlying pathogenic mechanisms but also vital therapeutic targets for [Parkinson’s disease].”
“Our study sheds light on the diversity of cell types, including [dopaminergic] neurons, in the [substantia nigra] and the complexity of molecular and cellular changes associated with [Parkinson’s disease] pathogenesis,” the authors concluded.
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