Association Between Toll-Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Genetic Variants and Clinical Progression of Huntington's Disease.

BACKGROUND: Although Huntington's disease (HD) is caused by a single dominant gene, it is clear that there are genetic modifiers that may influence the age of onset and disease progression. OBJECTIVES: We sought to investigate whether new inflammation-related genetic variants may contribute to the onset and progression of HD. METHODS: We first used postmortem brain material from patients at different stages of HD to look at the protein expression of toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2). We then genotyped the TREM2 R47H gene variant and 3 TLR4 single nucleotide polymorphisms in a large cohort of HD patients from the European Huntington's Disease Network REGISTRY. RESULTS: We found an increase in the number of cells expressing TREM2 and TLR4 in postmortem brain samples from patients dying with HD. We also found that the TREM2 R47H gene variant was associated with changes in cognitive decline in the large cohort of HD patients, whereas 2 of 3 TLR4 single nucleotide polymorphisms assessed were associated with changes in motor progression in this same group. CONCLUSIONS: These findings identify TREM2 and TLR4 as potential genetic modifiers for HD and suggest that inflammation influences disease progression in this condition. © 2019 International Parkinson and Movement Disorder Society.The research leading to these results has received funding the European Research Council under the European Union’s Seventh Framework Programme: FP/2007-2013 NeuroStemcellRepair (no. 602278) to RAB and Fonds du Québec en Recherche, Santé (FRQS) to JDO. RV has received funding from Alzheimer's Research UK. AK has been supported by a PhD scholarship from the Onassis Foundation and a studentship by the Alborada Trust, and currently funded by a grant from the Evelyn Trust. RAB has received grants from NIHR; MRC; Wellcome Trust; Parkinson's UK; Huntington's Disease Association; Rosetrees Trust; Cure Parkinson's Trust, royalties from Wiley and Springer-Nature and consultancy monies from LCT; F-Prime; Fujifilm Cellular Dynamics International and Oxford Biomedica. RAB is an NIHR Senior Investigator. JDO is receiving salary support from FRQS and Parkinson Québec. The Cambridge Brain Bank is supported in part by NIHR