NOVEL EXTRACELLULAR VESICLE AND MOLECULAR BIOMARKERS OF ENVIRONMENTAL EXPOSURE AND DISEASE PROGRESSION IN ALS

Project summaryAmyotrophic lateral sclerosis (ALS) is a predominantly sporadic condition affecting motor neurons (MNs). Itsetiology is unknown but several environmental neurotoxicants have been associated with ALS. Though, nonehave a clear pathogenic role. Only a few of the previous studies investigating the role of environmental factorsin ALS have assessed individual biomarkers of exposure (mostly to persistent pollutants) and none hasdemonstrated a direct concordance between signaling pathways produced by neurotoxic exposure andthose implicated in ALS. So far, the progress in this field is hampered by the lack of CNS-relevant specificbiomarkers for monitoring both environmental exposure to neurotoxicants and disease progression.Recently, we screened a series of highly prevalent neurotoxicants associated with ALS in vitro and found thatmouse and human MNs exhibit a preferential and dose-dependent vulnerability to the metals manganese (Mn)and arsenic (As), and several organophosphate (OP) and pyrethroid (PT) pesticides (e.g. chlorpyrifos [CPS]and cypermethrin). Also, we found that MNs expressing an incompletely penetrant familial ALS variant of TARDNA-binding protein 43 (G298S TDP-43) are vulnerable to As, Mn and CPS at very low doses that areinnocuous to wild-type MNs. TDP-43 pathology is a hallmark of the large majority of ALS cases, both familialand sporadic, so altogether our data suggest that these toxicants could be environmental modifiers ofmost of the forms of ALS. Intriguingly, excess metals and pathological proteins such as TDP-43 canboth be extruded from cells through a homeostatic mechanism that involves the release of tinymembrane-bound compartments called extracellular vesicles (EVs). EVs are now of particular interest asdisease biomarkers in other fields. CNS-derived EVs can be isolated from blood because of their ectopicmembrane expression of L1CAM. In this study, we will use biospecimens available in the US ALS NationalBiorepository and from the Target ALS brain bank to reach the following objectives: 1) we will validate hairas a useful biospecimen in ALS for the measure of poorly investigated non-persistent pollutants like OPsand PTs (200 patients x2; taken at 2 ALS stages); 2) we will examine the use of CNS-L1CAM-EVs isolatedfrom the blood of the same 200 patients (2 ALS stages) as a biomarker of environmental exposure(compare metal levels and profiles), as well as a biomarker of disease progression via the accumulation ofTDP-43; 3) our epidemiological and statistical analysis will determine association betweenenvironmental toxicants, TDP-43 and ALS progression; 4) we will examine concordance betweentoxicant-specific exposure extracted from gene-expression profiling in mice exposed to CPS and Mnand patient pathogenic transcriptional signatures obtained from our Target ALS consortium to identifydisease pathways with therapeutic potential for ALS. By elucidating molecular mechanisms andbiomarkers of environmental ALS, our study will have several far-reaching clinical and therapeutic implications.