Related Experiment Video
Updated: Dec 12, 2025
Cerebellar Regional Dissection for Molecular Analysis
Published on: December 5, 2020
Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in
Ricardo Mouro Pinto1,2, Larissa Arning3, James V Giordano1
1Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Insights
Somatic CAG expansion in Huntington's disease (HD) and spinocerebellar ataxia type 1 (SCA1) shows similar tissue instability patterns. Peripheral tissues may offer a viable source for measuring expansion in biomarker assays for HD therapeutics.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is caused by expanded CAG repeats in the HTT gene, with somatic expansion proposed to influence disease onset and progression.
- Understanding the mechanisms of somatic CAG expansion in the human central nervous system (CNS) and periphery is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the patterns and extent of CAG repeat expansion in various postmortem CNS and peripheral tissues from individuals with Huntington's disease.
- To compare CAG expansion profiles in HD with those in spinocerebellar ataxia type 1 (SCA1), a distinct repeat expansion disorder, to identify common or divergent mechanisms.
Main Methods:
- Quantitative analysis of CAG repeat expansion in approximately 50 central nervous system and peripheral tissues from eight individuals with Huntington's disease (seven adult-onset, one juvenile-onset).
- Assessment of ATXN1 CAG repeat expansion in brain regions of an individual with spinocerebellar ataxia type 1 (SCA1).
Main Results:
- Similar tissue instability profiles for CAG expansion were observed across all Huntington's disease individuals and were also present in the spinocerebellar ataxia type 1 individual.
- CAG expansion occurred in all analyzed tissues, with the highest instability noted in multiple cortical regions and the neostriatum (CNS) and the liver (periphery).
- The propensity for HTT CAG expansion in an individual is consistent across all tissues and in cerebrospinal fluid, suggesting disease locus-independent factors influence expansion.
Conclusions:
- Somatic CAG expansion patterns show conserved tissue instability across different repeat expansion disorders, indicating shared underlying mechanisms.
- CAG expansion alone is insufficient to cause specific cell type or disease pathology; distinct toxic processes triggered by varying repeat lengths across cell types and diseases likely contribute to pathology.
- Peripheral tissues and cerebrospinal fluid may serve as valuable sources for measuring CAG expansion as biomarkers for therapeutic development in Huntington's disease.
Abstract:
The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.
Related Concept Videos
01:28Disorders of the Nervous Tissue
Homeostatic Imbalances:
Alzheimer's disease manifests as a gradual decline in memory and cognitive abilities, attributed to the buildup of amyloid plaques and neurofibrillary tangles in the brain.
Parkinson's disease arises from the...
02:30Histone Variants at the Centromere
02:17Microtubule Instability
01:37Neural Regulation