About a century ago, Otto Loewi discovered in his laboratories in Graz, Austria, that nerve impulses are transmitted by chemical messengers like acetylcholine. Since then, the field of neuroscience has advanced significantly and the scientific interest in this research field rapidly grew. It became obvious that disturbed neurotransmission is a common characteristic of many neurodegenerative disorders like Alzheimer’s and Parkinson’s disease. Today it is known that not only acetylcholine but also several other neurotransmitters like serotonine, glutamate, and most importantly dopamine are essential for the development of Parkinson’s symptomatology. Besides neurotransmitters, several other clinical, imaging, biochemical, and genetic biomarkers play a role in Parkinson’s and help to distinguish this disorder, monitor disease progression, and measure positive responses of therapeutic interventions.
Symptomatic Parkinson’s Treatments
In the last decades, therapeutic approaches focused mainly on dopamine substitution, resulting in symptomatic medications like the well-known L-DOPA. Currently researchers are working on viral delivery systems for dopamine agonists to further improve the positive effects on motor symptoms. Interventions into the glutamate or serotonine systems of Parkinson’s patients can improve dyskinesia, rest tremor, or (as in the case of glutamate) even extend the effect of L-DOPA. The disadvantage of these symptomatic treatments lays in systemic and cognitive side effects that can make treatment inappropriate.
Disease-Modifying Treatments
Symptomatic treatments are able to improve the everyday life of Parkinson’s patients but don’t halt or even cure the disease. Researchers are therefore working on therapies that might slow disease progression, e.g. by infusion of neurotrophic factors into relevant brain regions. Neurotrophic factors have neuroprotective effects on dopaminergic cells and can thus halt or at least slow the dopaminergic cell loss observed in Parkinson’s patients. So far this therapy option has been successfully tested in animal models, but a positive effect in patients still has to be proven.
Personalized Treatment Options
After the development of these general treatment options, research focused more and more on personalized treatments.
Glucocerebrosidase
For example, the protein aggregation marker alpha-synuclein is well known, but new markers have emerged during the last few years. An interesting biomarker is glucocerebrosidase, an enzyme that plays an essential role in in the rare Gaucher disease. Recent research could show that mutations in the gene that encodes this enzyme are potential risk factors for the development of Parkinson’s disease because they influence alpha-synuclein degradation. Consequently, Parkinson’s patients with such mutations could be treated to increase glucocerebrosidase levels, thus improving degradation processes of alpha-synuclein and maybe leading to a reduction of phenotypic symptoms.
TREM2
Another interesting, recently discovered biomarker is TREM2. This protein might play a critical role for the development and progression of Parkinson’s disease and is largely expressed on microglia. TREM2 appears to be involved in clearing processes of dying neurons and neuroinflammation. TREM2 mRNA levels are very high in the substantia nigra and thus in the most affected brain region of Parkinson’s disease. People with genetic alterations of the TREM2 gene present large amounts of aggregates containing, for example, alpha-synuclein and neurofilament (two biomarkers of Parkinson’s disease).
Neurofilament Light Chain Protein
Recently the neurofilament light chain protein has been highly discussed as a biomarker for Parkinson’s. Since this protein seems to be a biomarker for several neurodegenerative diseases, including Alzheimer’s and Huntington’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, and multiple sclerosis, its role seems to be more general and probably not relevant for personalized Parkinson’s treatment.
Future research will need to reveal if glucocerebrosidase, TREM2, and neurofilament light chain can live up to contemporary views regarding their potential impact on specialized Parkinson’s disease treatment research. The use of these proteins as biomarkers in clinical and preclinical studies already adds value to current Parkinson’s disease research.
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