Huntington disease (HD) is a rare, genetic, autosomal dominant neurodegenerative disease, caused by an unstable CAG repeat expansion in the HTT gene. Over the past decade, somatic instability has become a major focus of investigation. Large genome-wide association studies together with work on post-mortem tissue, animal and cellular models, have brought this mechanism to the forefront, linking it to age at onset, disease severity and progression, reshaping our understanding of HD as a dynamic DNA-driven process over the lifetime, and highlighting it as a potentially actionable target. However, the extent of its causal contribution and precisely how it contributes to disease pathogenesis remain incompletely understood. This review focuses on the current understanding of the mechanisms driving somatic expansion, its consequences, the tissue-specific patterns of instability and their clinical impact, while critically considering the evidence for, and limitations of, its role in disease pathogenesis and emerging therapeutic strategies targeting repeat instability.
Cortical malformations are a frequent cause of infantile drug-resistant epilepsy. Somatic variants in only a fraction of brain cells are now an established cause of cortical malformations found in epilepsy surgical resections. Recent major technological and conceptual advances have improved our understanding of such mosaic neurodevelopmental disorders. Here, we review the genetics and neuropathology of focal cortical malformations caused by somatic mosaicism, focusing on the mechanistic target of rapamycin (mTOR) pathway-related focal cortical dysplasia type II and the glycosylation-defective mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). We discuss technical implementations and remaining challenges in the detection of low-level somatic variants and highlight how single-cell approaches have provided new insights into the disease mechanisms. Further, we cover the recent in vivo efforts to better characterize MOGHE, a newly defined cortical malformation.
Somatic mutations in major neurodegenerative diseases are poorly understood, but research over the past 2 years provides valuable insights. Single-cell whole-genome sequencing of vulnerable neurons in Alzheimer’s disease and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) revealed excess accumulation of single-nucleotide variant signatures and two-bp deletions independent of pathogenic protein aggregation. Increased oxidative DNA damage and possibly impaired DNA damage repair pathways may explain more pronounced signatures in patients. Ultra-deep sequencing of disease-associated genes in relevant tissues in ALS/FTD identified a subset of sporadic patients carrying mosaic variants that cause disease when present in the germline, but the pathogenicity of such mosaic variants at low allele frequencies is unclear. Research on somatic variants in Parkinson’s disease remains underrepresented in the literature.
Retinal circuits extract visual features such as color, contrast, and motion. Direction-selective (DS) circuits provide a well-studied model for understanding how the brain builds feature-selective circuits. Recent work highlights the remarkable evolutionary conservation of DS circuit components. Across species, these circuits share common transcriptional programs that diversify DS cell types and molecular cues that help establish precise synaptic organization. Directional tuning emerges during development without visual input through gene regulatory networks, extracellular signaling, and activity-dependent mechanisms. Disruption of these processes can impair motion processing and contribute to visual and oculomotor deficits. Therefore, DS circuits provide a powerful system for dissecting the molecular programs involved in neuronal subtype diversification, neurite guidance, and synaptic development. In this review, we summarize recent advances in our understanding of DS circuits, their development, cell type composition, and tuning across species.
