DYT-THAP1 dystonia is a monogenetic form of dystonia, a movement disorder characterized by the involuntary co-contraction of agonistic and antagonistic muscles. The disease is caused by mutations in the THAP1 gene, although the precise mechanisms by which these mutations contribute to the pathophysiology of dystonia remain unclear. The incomplete penetrance of DYT-THAP1 dystonia, estimated at 40 to 60 %, suggests that an environmental trigger may be required for the manifestation of the disease in genetically predisposed individuals. To investigate the gene-environment interaction in the development of dystonic features, we performed a sciatic nerve crush injury in a genetically predisposed DYT-THAP1 heterozygous knockout mouse model (Thap1+/-). We employed a multi-omic assessment to study the pathophysiological pathways underlying the disease. Phenotypic analysis using an unbiased deep learning algorithm revealed that nerve-injured Thap1+/- mice exhibited significantly more dystonia like movements (DLM) over the course of the 12-week experiment compared to naive Thap1+/- mice. In contrast, nerve-injured wildtype (wt) mice only showed a significant increase in DLM compared to their naive counterpart during the first weeks after injury. Furthermore, at week 11 after nerve crush, nerve-injured Thap1+/- mice displayed significantly more DLM than nerve-injured wt counterparts. Multi-omic analysis of the cerebellum, striatum and cortex in nerve-injured Thap1+/- mice revealed differences that are indicative of an altered energy metabolism compared to naive Thap1+/- and nerve-injured wt animals. These findings suggest that aberrant energy metabolism in brain regions relevant to dystonia may underlie the dystonic phenotype observed in nerve injured Thap1+/- mice.
Keywords: DYT-THAP1; Dystonia; Energy metabolism; Multi-omic; Nerve injury; Second-hit hypothesis.
Copyright © 2024. Published by Elsevier Inc.