Abnormal molecular signatures of inflammation, energy metabolism, and vesicle biology in human Huntington disease peripheral tissues.

BACKGROUND: A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examine whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. RESULTS: We generate large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients-those most likely involved in clinical trials. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirms the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observe changes in the homeostasis of extracellular vesicles, where we find consistent changes of genes and proteins involved in this process. In-depth single nucleotide polymorphism data across the HTT gene are derived from the generated primary cell lines. CONCLUSIONS: Our 'omics data document the involvement of inflammation, energy metabolism, and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. The generated data, complemented by the primary cell lines established from peripheral tissues, and a large panel of iPSC lines that can serve as human models of HD are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis.

Mitochondrial cristae remodelling is associated with disrupted OPA1 oligomerisation in the Huntington's disease R6/2 fragment model.

There is evidence of an imbalance of mitochondrial fission and fusion in patients with Huntington's disease (HD) and HD animal models. Fission and fusion are important for mitochondrial homeostasis including mitochondrial DNA (mtDNA) maintenance and may be relevant for the selective striatal mtDNA depletion that we observed in the R6/2 fragment HD mouse model. We aimed to investigate the fission/fusion balance and the integrity of the mitochondrial membrane system in cortex and striatum of end-stage R6/2 mice and wild-type animals. Mitochondrial morphology was determined using electron microscopy, and transcript and protein levels of factors that play a key role in fission and fusion, including DRP1, mitofusin 1 and 2, mitofilin and OPA1, and cytochrome c and caspase 3 were assessed by RT-qPCR and immunoblotting. OPA1 oligomerisation was evaluated using blue native gels. In striatum and cortex of R6/2 mice, mitochondrial cristae morphology was abnormal. Mitofilin and the overall levels of the fission and fusion factors were unaffected; however, OPA1 oligomerisation was abnormal in striatum and cortex of R6/2 mice. Mitochondrial and cytoplasmic cytochrome c levels were similar in R6/2 and wild-type mice with no significant increase of activated caspase 3. Our results indicate that the integrity of the mitochondrial cristae is compromised in striatum and cortex of the R6/2 mice and that this is most likely caused by impaired OPA1 oligomerisation.

Selective striatal mtDNA depletion in end-stage Huntington's disease R6/2 mice.

In Huntington's disease (HD) the striatum and cortex seem particularly vulnerable. Mitochondrial dysfunction can also cause neurodegeneration with prominent striatal involvement very similar to HD. We first examined if mitochondrial biogenesis, mitochondrial DNA (mtDNA) transcription, and the implications for mitochondrial respiratory chain (MRC) assembly and function differ between the striatum and cortex compared with the whole brain average in the healthy mouse brain. We then examined the effects of the mutant huntingtin transgene in end-stage R6/2 mice. In wild-type mice, mitochondrial mass (citrate synthase levels, mtDNA copy number) was higher in the striatum than in the cortex or whole brain average. PGC-1α and TFAM mRNA levels were also higher in the striatum than the whole brain average and cortex. mRNA reserve for MRC Complex proteins was higher in the striatum and cortex. In addition, in the cortex a greater part of mitochondrial mass was dedicated to the generation of ATP by oxidative phosphorylation than in the striatum or on average in the brain. In the HD transgenic striatum there was selective mtDNA depletion without evidence that this translated to abnormalities of steady-state MRC function. Our data indicate that in mice the striatum differs from the cortex, or whole brain average, in potentially important aspects of mitochondrial biology. This may contribute to the increased vulnerability of the striatum to insults such as the HD mutation, causing selective striatal mtDNA depletion in end-stage R6/2 mice.