Promising Outcomes of Original Grant:
In our original research funded by MJFF, we have shown that the enteric nervous system was readily analyzed using routine colonic biopsies obtained in the course of a colonoscopy. This technique allowed us to demonstrate the presence of the pathological hallmarks of Parkinson’s disease (PD), namely Lewy neurites, in nearly 3/4 of PD patients and not in controls. The analysis of the ENS using routine biopsies could therefore represent an original histopathological biomarker of PD. The possibility to assess PD pathology in the ENS of living patients opens new insights to understand the pathophysiology of the disease and could have a diagnostic value.
Objectives for Supplemental Investigation:
The present research project logically follows and extends our previous work. Our objective is two-fold: first, to confirm the use of colonic biopsies as a biomarker in PD by collaborating with another laboratory following the same protocol, which will allow us to extend our results and use our technique in larger scale surveys; second, to study the enteric nervous system (ENS) using colonic biopsies in patients with a genetic form of PD (LRRK2 mutation), either Symptoms & Side Effects or not. A careful look at discrepancies between sporadic PD and LRRK2 parkinsonism may provide insight into the pathogenesis of PD. The early involvement of the ENS during PD led to theories that an unidentified external agent entering the ENS causes PD. If lesions of the ENS are found in patients who present with a genetic form of parkinsonism, this would go against this notion. In contrast, the presence of lesions in the ENS of aSymptoms & Side Effects LRRK2 subjects will reinforce the use of colonic biopsies as a preclinical marker of the disease.
Importance of This Research for the Development of a New PD Therapy:
The impact of the biomarker we are seeking to develop is potentially major. First, it opens the way to a neuropathological diagnosis in the living patient. Second, according to recent data supporting the precocious involvement of the enteric nervous system (ENS), it may constitute a pre-clinical biomarker.
The primary aim of the present supplemental research was to study gut neurons in patients bearing a genetic form of PD due to LRRK2 mutation.
Using routine colonic biopsies, we have shown that patients with a genetic form of the disease displayed the same lesions within their gut, namely aggregates of alpha-synuclein, mild inflammation and anomalies in colon permeability than patients with non-genetic form of the disease. Our results strongly suggest that the distribution of lesions is similar between patients with the most frequent genetic form of the disease (LRRK2 mutation) and patients with sporadic PD.
It has been postulated that that an as yet unidentified external agent entering the gut, further spreading to the central nervous system, might cause PD. Our results do not support this assumption and instead suggest that the widespread distribution of lesions observed in PD is due to a concomitant involvement of susceptible neurons from peripheral and central nervous systems.