World Parkinson’s Disease Day | Exploring New Frontiers with Single-Cell Transcriptomics

April 11 marks World Parkinson’s Disease Day—a global initiative to raise awareness of one of the most prevalent and complex neurodegenerative disorders. Parkinson’s disease (PD) currently affects over 10 million people worldwide, with incidence rising sharply with age¹². As global populations continue to age, the burden of PD is expected to grow substantially, highlighting the urgent need for a deeper understanding of its pathogenesis and the development of more effective diagnostic and therapeutic strategies.

A Complex Disease with Many Unknowns

Clinically, PD is defined by progressive motor symptoms—such as tremors, rigidity, and bradykinesia—as well as a spectrum of non-motor features, including cognitive decline, mood disturbances, and gastrointestinal dysfunction¹. While the degeneration of dopaminergic neurons in the substantia nigra remains a central pathological hallmark, recent research has revealed that PD is a far more heterogeneous and systemic disorder than previously recognized³.

In recent years, studies exploring PD pathogenesis have expanded beyond a purely neuron-centric view. Current research directions include investigating the role of neuroinflammation⁴, glial cell dysfunction, transcriptomic alterations in both familial and sporadic PD⁴, and the gut-brain axis, including microbial influences⁵. Additionally, there is growing interest in identifying early biomarkers to enable patient stratification and personalized treatment approaches (Figure 1). To address these challenges, researchers are increasingly turning to next-generation technologies such as single-cell RNA sequencing (scRNA-seq), which provides unprecedented resolution for dissecting the cellular and molecular complexity of PD.

Figure 1. Molecular mechanisms involved in Parkinson disease².

Decoding PD with Single-Cell Transcriptome

Unlike bulk RNA sequencing, which averages signals across diverse cell populations, single-cell transcriptomics enables gene expression profiling at the resolution of individual cells, uncovering rare subpopulations, intermediate states, and lineage relationships critical to disease progression.

In a landmark study published in Brain, researchers profiled over 41,000 single-nuclei transcriptomes from post-mortem midbrain tissue of idiopathic PD patients (Figure 2). They identified a disease-specific neuronal cluster (CADPS2⁺/TH⁻) and widespread glial activation. PD-associated genetic risk loci were enriched in both neurons and glial cells, with microglia and astrocytes exhibiting stress-related and pro-inflammatory signatures—suggesting pan-glial activation as a key driver of disease pathology⁶.

Figure 2. Cell type composition of human midbrain⁶

Moreover, non-coding RNAs, especially long non-coding RNAs (lncRNAs), have attracted growing attention for their regulatory roles in PD. For example, MALAT1 has been implicated in multiple pathways including neuroinflammation and mitochondrial function (Figure 3), showing potential as a biomarker and therapeutic target⁷.

Figure 3. Schematic of various pathways that are affected by MALAT1 dysregulation in PD⁷

However, most commercially available single-cell transcriptome platforms lack the ability to effectively detect non-coding RNAs, limiting insights into regulatory networks involved in disease. At M20 Genomics, our VITA Single-Cell Transcriptome Sequencing Platform leverages random primers for RNA capture, enabling detection of a broad range of RNA species—including mRNAs, lncRNAs, and other noncoding RNAs (Figure 4)—from both fresh and FFPE tissues. This allows researchers to explore the regulatory roles of lncRNAs in cell-type-specific disease processes with greater depth and precision.

Figure 4. Counts of different RNA biotypes detected in mouse kidney FFPE samples with VITA platform⁸

The Microbiome Connection: A Gut Feeling

In addition to CNS- and immune-focused studies, the gut microbiome has emerged as a compelling area of investigation in PD research. Accumulating evidence suggests that intestinal dysbiosis may contribute to disease onset years before motor symptoms appear. Epidemiological studies have shown that inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease increase the risk of developing PD by 22–35%⁹.

A pivotal animal study demonstrated that gut microbiota contributes to PD pathogenesis by promoting motor dysfunction, neuroinflammation, and α-synuclein aggregation. Notably, microbiota transplants from PD patients worsened symptoms in α-synuclein-overexpressing mice, while antibiotics alleviated them (Figure 5)—highlighting gut-brain interactions and the microbiome as a modifiable risk factor¹⁰.

Figure 5. Illustration of gut microbiota regulating motor deficits and neuroinflammation in a model of PD¹⁰

Further, researchers have explored new therapeutic approaches centered on gut-derived dopamine production. In one study, oral berberine (BBR) was shown to boost L-dopa biosynthesis in the gut by enhancing BH4-mediated tyrosine hydroxylase activity in Enterococcus species (Figure 6). This gut-derived L-dopa entered the brain and elevated striatal dopamine levels, significantly improving motor symptoms in PD mice. When combined with targeted gut bacterial supplementation, BBR's effect was even more pronounced, positioning it as a vitamin-like adjunct therapy¹¹.

Figure 6. Changes in the intestinal bacterial composition as a result of BBR treatment ¹¹

While these findings are promising, current microbiome research technologies often lack single-bacterium resolution, limiting our ability to dynamically observe microbial functional changes during disease.

To overcome these limitations, M20 Genomics launched the VITA Gutmicrobiome Single-Bacterium Transcriptome Sequencing Product in 2023. This technology enables dynamic, high-resolution monitoring of gut microbial transcriptional activity at the single-bacterium level, allowing researchers to capture key transcriptomic changes over time.

A study published in Protein & Cell using the VITA Gutmicrobiome Platform firstly established a single-cell transcriptional landscape of the human gut microbiome, profiling 29,742 individual microbes spanning 329 unique species. This work offers unprecedented insights into microbial heterogeneity and functional dynamics within complex microbial communities.

Figure 7. Bacterial gene expression landscape in a human gut microbiome¹²

Combined with our ability to profile both host and microbial single-cell transcriptomes, VITA offers an integrated solution to unravel the gut-brain axis in PD with unprecedented precision.

Looking Ahead

Understanding the cellular and molecular heterogeneity of Parkinson’s disease is critical for the development of targeted, personalized therapies. With single-cell transcriptome technologies, scientists are now able to investigate PD from multiple dimensions—brain, blood, and gut—at single-cell resolution, identifying early biomarkers, redefining disease subtypes, and exploring novel intervention strategies. As these tools become more accessible, we anticipate a transformative impact on translational research and clinical innovation in PD.

At M20 Genomics, we remain committed to enabling the next generation of neurodegenerative disease research through cutting-edge single-cell and spatial transcriptomic solutions. This World Parkinson’s Day, we reaffirm our mission to support the scientific community in decoding the complexity of diseases like PD—one cell at a time.

Reference:

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