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There is fresh hope for treating Huntington’s disease, an inherited neurodegenerative condition that causes uncontrollable movements, emotional disturbance and the loss of mental abilities. But biological mysteries remain.
This Nature Outlook is editorially independent. It is produced with third party financial support. About this content.
Roche in partnership with Ionis Pharmaceuticals is committed to supporting the needs of the community living with Huntington’s disease (HD) and developing treatments for those affected by this devastating disease. We invited journalist and HD patient advocate Charles Sabine to give his perspective at an event organized at Roche in recognition of World Rare Disease Day 2018.
Direct conversion of adult Huntington’s disease patient fibroblasts into medium spiny neurons recapitulates hallmark phenotypes such as cell death, in contrast to models that lack epigenetic markers of aging. This successful ‘disease-in-a-dish’ highlights the benefits of capturing age in an adult-onset disorder model.
Two decades after antisense oligonucleotides (ASOs) were initially identified as agents capable of modulating RNA processing and protein expression, the first antisense oligonucleotide (ASO) therapies have now been approved for the treatment of neurological disease. Here, Rinaldi and Wood discuss our current understanding of ASO pharmacology, and the future prospects for ASO-mediated treatment of neurological disease
Different types of reactive astrocyte are generated after various injuries and insults to the brain, but less is known about what these astrocyte subtypes do. Here, Shane Liddelow et al. describe how these reactive astrocytes are induced by neuroinflammatory microglia. The authors also explore the functional roles of reactive astrocytes in the progression of disease or damaged states, and show that A1 astrocytes contribute to the death of neurons in the central nervous system under certain conditions.
Compromised compartmentalization of nucleus and cytoplasm has emerged as a central feature of aging and neurodegenerative diseases. Nucleocytoplasmic transport is disrupted, with widespread mislocalization of nuclear pore proteins, in TDP-43 proteinopathies such as, amyotrophic lateral sclerosis and frontotemporal dementia.
The Huntington's disease (HD) induced pluripotent stem cell (iPSC) consortium describe the combined use of differentiated patient-derived iPSCs and systems biology to discover underlying mechanisms in HD. They identify neurodevelopmental deficits in HD cells that can be corrected in cells and in vivo with a small molecule.
Direct neuronal conversion of skin fibroblasts from individuals with Huntington’s disease (HD) generates a population of medium spiny neurons that recapitulate hallmarks of HD, including aggregation of mutant huntingtin protein, DNA damage and spontaneous cell death.
Huntingtin (HTT) is a large protein, essential for embryonic development and involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and transcription regulation. The large number of HTT interactors that have been identified suggests that HTT is at the centre of a protein–protein interaction hub. A mutation in the HTT gene results in the expansion of a polyglutamine repeat at the N-terminus of HTT and in Huntington's disease. Stefan Kochanek and colleagues present the full-length structure of human HTT in a complex with HAP40 to 4 Å resolution. This detailed structure paves the way for an improved understanding of the diverse cellular functions of HTT.
Huntington disease is an autosomal dominant neurological disorder caused by mutation in HTT. The disease typically manifests in adulthood and is characterized by progressive motor, cognitive and behavioural impairment. This Primer discusses the current knowledge of this disease.