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Mov Disord. 2020 Mar;35(3):401-408. doi: 10.1002/mds.27911. Epub 2019 Nov 14.

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.

Author information

1
John van Geest Centre for Brain Repair & Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
2
Medway School of Pharmacy, University of Kent at Medway, Kent, United Kingdom.
3
Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada.
4
Department of Pathology, Cambridge University Hospitals NHS (National Health Service) Foundation Trust, Cambridge, United Kingdom.
5
Integrated Systems Engineering, Milano, Italy.
6
Institute for Genetic and Biomedical Research - CNR, Milano, Italy.

Abstract

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.

KEYWORDS:

Huntington; TLR4; TREM2; cognitive decline; inflammation; motor symptoms

PMID:
31724242
DOI:
10.1002/mds.27911

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