van Roon-Mom, W. | Search bioRxiv

bioRxiv2024

Polyglutamine expansion induced dynamic misfolding of Androgen Receptor

Spinal bulbar muscular atrophy (SBMA) is caused by a polyglutamine expansion (pQe) in the N-terminal transactivation domain of human androgen receptor (AR-NTD), resulting in a combination of toxic gain- and loss-of-function mechanisms. The structural basis of these processes has not been resolved due to the disordered nature of the NTD, which hinders experimental analyses of its detailed conformations. Here, using extensive computational modelling, we show that AR-NTD forms dynamic compact regions, which upon pQe re-organize dynamically, mediated partly by direct pQ interaction with the Androgen N-Terminal Signature (ANTS) motif. The altered dynamics of the NTD result in a perturbation of interdomain interactions, with potential implications for binding of the receptor protein to its response element. Oligomeric aggregation of the dynamic misfolded NTD exposes pQe, but blocks tau-5 and the FQNLF motif, which could lead to aberrant receptor transcriptional activity. These observations suggest a structural mechanism for AR dysfunction in SBMA.

pathology↗

bioRxiv2022

Mapping the glial transcriptome in Huntington's disease using snRNAseq: Selective disruption of glial signatures across brain regions

Huntingtons disease (HD) is a severely debilitating, autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from people with HD, and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight two possible mechanisms that characterise the glial contribution to disease pathology. Firstly, we show that upregulation of molecular chaperones represents a cross-glial signature in HD, which likely reflects an adaptive response to the accumulation of mutant Huntingtin (mHTT). Secondly, we show an oligodendrocyte-specific upregulation of the calmodulin-dependent 3,5-cyclic nucleotide phosphodiesterase 1A (PDE1A) in HD brain compared to controls, which may cause dysfunction of key cellular functions due to the downregulation of the important second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease. As glia are more tractable to treat than neurons, our findings may be of therapeutic relevance.

neuroscience↗