Huntingtin is a cell-autonomous regulator of neuropeptide trafficking and clock output

Structure-function dissection of huntingtin exon 1 identifies a PRD-driven modifier of neuronal toxicity in Huntington’s disease

The Huntingtin gene (HTT) contains a conserved, yet expandable CAG repeat within exon 1. While the pathogenic expansion in Huntington’s Disease (HD) is well studied, the role of surrounding domains remains unclear. Using genome-edited mini-organoids and neurons, we dissected HTT exon 1 and found species-specific toxicity: the human variant caused more severe deficits than the mouse. Swapping the proline-rich domain (PRD) - the most divergent region - revealed its key role: the mouse PRD mitigated, while the human PRD worsened neuronal phenotypes. Omics profiling showed that pathogenic human exon 1 induced broad protein dysregulation, largely reversed by mouse PRD replacement. Bioinformatics implicated the actin cytoskeleton and transcriptional coactivator MKL2/MRTFB. We validated MKL2/MRTFB dysregulation in HD models and showed that restoring its expression rescued neuronal abnormalities. These findings highlight the PRD’s contribution to HD toxicity and point to MKL2/MRTFB and the cytoskeleton as candidate mediators.

Mutant Huntingtin disrupts neurogenic and astroglial programs via the EZH2-Let-7g-LIN28 axis with rescue by epigenetic modulators.

It is shown that neurogenesis is disrupted at multiple stages of lineage progression in both rodent and human neural stem cell models of Huntington's disease, and a panel of clinically relevant epigenetic compounds hold promise for stage-spanning therapeutic strategies capable of modifying disease trajectory.

The Role of PolyQ in Global Conformational Dynamics and Stability of Huntingtin.

Huntington's disease (HD) is known for its abnormal polyQ stretch in the first exon of the HTT gene. HD is listed among the fatal autosomal dominant neurodegenerative disorders targeting the central nervous system and interfering with motor, cognitive, and psychiatric functions. The HTT gene codes for Huntingtin (Htt), a large three-domain protein with a polyQ stretch present in the N-terminal domain. In diseased cells, inclusion bodies are enriched in Htt fragments containing an extended polyQ region. The expansion of the polyQ correlates with aggregate size and onset of HD. However, the exact role of the full-length Htt in aggregate formation has not been fully known. Using coarse-grained molecular dynamics simulations at the near-atom level, our study indicates that the conformational dynamics of Htt─twisting and open-close motions of the domains─are dependent on the length of polyQ. In the presence of HAP40, the global conformational landscape is restricted, and the degree of dependence on polyQ length is low. The intra- and intercontact analyses suggest that the polyQ region can loop like a hairpin with a higher probability for a larger polyQ length. However, the looping probability is reduced in the presence of HAP40 due to increased contacts between polyQ and other regions of Htt. Thus, our findings indicate that polyQ has a significant role in the disease's pathogenesis, which includes altered functional activity and structural modifications leading to inclusion body formation. These effects can be controlled with the help of HAP40.

Molecular mechanisms of neurodegeneration in Huntington’s Disease

Heat shock factor 1 (HSF1) plays a pivotal role in maintaining neuronal health, and its dysfunction contributes significantly to the progression of Huntington’s disease. Rocio Gomez-Pastor tells us more. Huntington’s disease (HD) is a devastating, inherited neurodegenerative disorder marked by progressive motor dysfunction, cognitive decline, and psychiatric symptoms. At its genetic core lies a mutation in the huntingtin (HTT) gene, specifically an expansion of CAG trinucleotide repeats that encode an abnormally long polyglutamine (polyQ) tract in the huntingtin protein. (1) This mutation transforms an otherwise essential cellular protein into a toxic species prone to misfolding and aggregation. Over time, these molecular disturbances selectively damage neurons, particularly in the striatum and cortex. (2,3)

Biphasic Temporal Remodeling Of The Proteome In A Polyglutamine-Expanded Huntingtin In Vitro Aggregation Cell Model: From Early Rna-Regulatory Compensation To Selective Mitochondrial Energy Failure

Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model

The most common genetic cause of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G4C2 repeat in the first intron of the gene C9orf72. The C9orf72 repeat expansion is bidirectionally transcribed into sense and anti-sense RNA foci, and also produces dipeptide repeats (DPRs) via a non-canonical translation mechanism known as repeat-associated (RAN) translation. Each of these components of the G4C2 repeat expansion cause neurodegenerative effects in animal models when expressed in neurons, but impacts from glial expression are more poorly understood. Here, we use glial cell type-specific expression of individual DPRs, of RNA repeat-only, or of the G4C2 repeat, that produces both DPRs and RNA repeats, to systematically investigate glial toxicity of each component. We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia. Each of these transgenes are capable to produce the GR DPR, which also is the most toxic factor in neurons. We demonstrate that both the GR and G4C2 transgenes cause activation of mdg4, an endogenous retrovirus (ERV). Such ERV expression is a hallmark of TDP-43 dysfunction that is commonly observed in C9orf72 patients. We find that glial expression of either the GR or the G4C2 transgene is toxic to glial cells, but such expression does not cause loss nearby neurons. However, blocking apoptotic signaling within glia that express either GR or G4C2 via expression of the p35 caspase inhibitor further exacerbates effects on lifespan and ablating such glia via expression of the proapoptotic reaper gene partially ameliorates these effects. Together, these results indicate that expression of toxic C9orf72 components in glia produces deleterious effects on lifespan, though potentially through different mechanisms than seen in TDP-43 models of ALS/FTD.