What is Parkinson’s Disease?
Parkinson’s Disease (PD) is a common neurodegenerative disorder characterized by difficulty with motor functions, impaired balance, and muscle stiffness. It is the fastest-growing neurodegenerative disorder and the second most common one, affecting approximately 8.5 million people globally. PD is associated with a general life expectancy of only 7 to 14 years following diagnosis. Despite the challenges posed by this disease, substantial investments and efforts from organizations such as the Michael J Fox Foundation have resulted in rapid advancements in PD pathology, biomarkers, and effective treatments.
PD was first described in 1817 and is pathologically classified as neurodegeneration or loss of dopamine-producing neurons or nerve cells which control movement. It is a multifactorial process linked to both genetic and environmental factors, however, there has still been no direct cause of PD clearly defined. Due to the highly varied nature of PD and its clinical presentation, reliable diagnostic tests and biomarkers are still difficult to link to the disease.
The Michael J Fox Foundation has invested over $1 billion dollars in the pursuit of a cure for PD. The global approach to combating PD includes a better definition of disease biology, onset, biomarkers and treatment.
PD patients have been treated with levodopa and carbidopa since the 1960s. The drugs raise dopamine levels and help alleviate symptoms but cannot cure the disease. New treatments include gene replacement therapy to reintroduce defective enzymes linked to disease pathology including β-glucocerebrosidase. There are currently at least 500 planned or ongoing clinical trials searching for new treatments for PD.
In order to effectively treat patients as soon as possible, diagnostic and prognostic biomarkers are crucial. PD diagnosis can currently only happen once the disease has manifested, often years after the start of the neuron damage. Early biomarkers are therefore extremely useful for patients and treating doctors. The field of biomarkers for PD continues to evolve and Synexa is passionate about finding innovative solutions to help combat this disease by leveraging our experience in biomarker identification and validation.
Established biomarkers of Parkinson’s disease
Diagnostic biomarkers for PD in both blood biofluids and cerebrospinal fluid include types of alpha-synuclein (α-syn). Aggregation of α-syn due to misfolding accumulates in neural cells to toxic levels, causing neuronal cell death, thereby playing a central role in the development of PD. Alpha-synuclein can exist in multiple forms with increases in oligomeric α-syn pathologically implicated in the progression of PD. Classical biomarkers of Alzheimer’s disease are similarly associated with PD, including neurofilament light chain and tau. Whilst measurement of these biomarkers can be achieved through conventional ligand binding assay kits, quantification of oligomeric α-syn presents a significant bioanalytical challenge.
Measurement of oligomeric α-syn
Oligomers are often present at low concentrations and are transient and unstable, therefore any assay or test will need to be sensitive and robust. Using oligomer-specific detection antibodies will also be vital to distinguish the diseased form of α-syn from total α-syn. Synexa has developed assays to measure several of the PD biomarkers and specialises in developing sensitive, bespoke assays such as those required for oligomeric α-syn. Measuring α-syn and other biomarkers in cerebrospinal fluid remains a challenge. Collection of these samples is invasive and often results in small volumes for analysis. An alternative source of these biomarkers would therefore be beneficial for the patients and analytical lab.
Exosomes package α-syn and may contribute to disease progression
Exosomes are released from nearly all cell types and are composed of a lipid membrane and package a multitude of proteins, nucleic acids and signalling molecules between cells. Exosomes provide the ideal environment for the aggregation of α-syn and therefore, the formation of oligomeric α-syn. Oligomeric α-syn is more easily taken up by recipient neuronal cells than free α-syn. Cells unable to eliminate the oligomers or those that accelerate their release in exosomes therefore further exacerbate neurodegeneration.
The isolation of neuronal exosomes and analysis of their “payload” which may include various forms of α-syn could potentially be very useful in the early diagnosis of PD-related neurodegeneration. At Synexa, we support both the isolation and characterisation of exosomes, but also multiple assay platforms to quantify exosome payload.
Scientists continue to learn more about how α-syn may accumulate and how it contributes to PD along with other biological and environmental factors. Recently, it has been revealed that the gut-brain axis plays a central role in many neurological diseases, including PD.
Gut microbiome and the onset of PD
It is hypothesized that dysbiosis (unbalanced microbial population) may predate the clinical symptoms of PD. Many studies have shown differences in the microbiota between PD patients and healthy controls, however, there remains no clear consensus on which bacteria are enriched or reduced in PD patients. A recent meta-analysis found that butyrate-producing species are reduced in PD patients. Butyrate is the primary energy source of intestinal epithelial cells and a reduction of butyrate availability leads to less efficient barrier function due to lower metabolic activity of the epithelium. This leads to the so-called “leaky gut” phenomenon, where molecules that are normally kept inside the GI tract, can now cross the barrier to the outside and cause inflammation, which is a hallmark of PD.
A very recent study found that inflamed intestinal epithelium produced more modified oligomeric α-synuclein than the healthy epithelium. The enteric nerves are in close proximity to the epithelium and the α-synuclein may enter the nervous system here and thereafter accumulate in the brain. In mice, prevention of intestinal inflammation showed improved motor performance, demonstrating the importance of controlling the gut microbiome in PD.
Conclusions
Synexa is passionate about unique biomarker identification. Our varied approaches to analysis and experiences with multiple sample types allow us to support our clients interested in both treating and better understanding PD. On World Parkinson’s Day, we acknowledge the ever-present need to find a cure for this debilitating disease as well as improving global knowledge on early detection, novel treatments, disease response and patient wellness.
Co-authored by Nicholas Woudberg, Head of Scientific Strategies, and Gert Pretorious, Senior Scientist (Genomics) at Synexa Life Sciences.
References:
- Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548–60.
- Danzer, K.M., Kranich, L.R., Ruf, W.P. et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegeneration. 2012. 7, 42.
- https://www.michaeljfox.org/ [Accessed: 06Apr2023].
- Parnetti L, Gaetani L, Eusebi P, Paciotti S, Hansson O, El-Agnaf O, Mollenhauer B, Blennow K, Calabresi P. CSF and blood biomarkers for Parkinson’s disease. Lancet Neurol. 2019 Jun;18(6):573-586.
- Romano S, Savva GM, Bedarf JR, Charles IG, Hildebrand F, Narbad A. Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation. NPJ Parkinsons Dis. 2021 Mar 10;7(1):27.
- Shi J, Wang Y, Chen D, Xu X, Li W, Li K, He J, Su W, Luo Q. The alteration of intestinal mucosal α-synuclein expression and mucosal microbiota in Parkinson’s disease. Appl Microbiol Biotechnol. 2023 Mar;107(5-6):1917-1929.
- Stefanis L. α-Synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med. 2012 Feb;2(2):a009399.
- Tan AH, Hor JW, Chong CW, Lim SY. Probiotics for Parkinson’s disease: Current evidence and future directions. JGH Open. 2020 Nov 20;5(4):414-419.
- https://www.who.int/news-room/fact-sheets/detail/parkinson-disease [Accessed: 06Apr2023].
