Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1

Abstract

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

Selective forces acting on spinocerebellar ataxia type 3/Machado–Joseph disease recurrency: A systematic review and meta‐analysis

“…The result of instability in most tissues was toward expansions, although the tendency for the predominance of contractions has been seen in ovaries and testicles of HD transgenic mice 52 . In humans, the study of HD cases was more focused on assessing the expansion and not the instability 51 . Even so, this study described that the gonads presented low expansion rates, with the exception of a subject with juvenile HD and a large original expansion.…”

“…Although rarely obtained in SCA3/MJD, results of studies on somatic mosaicism in polyglutaminopathies could be seen as an indirect support for speculation on the way instability during meiotic cell divisions may affect the repeats. Post‐mortem studies in affected patients by SCA3/MJD, and especially in those with Huntington's disease and SCA1, revealed the presence of expanded CAG repeat instabilities in multiple tissues 49‐51 . The result of instability in most tissues was toward expansions, although the tendency for the predominance of contractions has been seen in ovaries and testicles of HD transgenic mice 52 .…”

Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice

“…Recent genome-wide association studies (GWAS) for modifiers of HD onset highlight somatic CAG expansion as a key driver of the rate of disease onset ( Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium, 2019 ). Genetic data from these GWAS as well as extensive cross-tissue analyses of somatic instability ( Mouro Pinto et al, 2020 ) support a two-step model of HD pathogenesis whereby cellular vulnerability is determined by both the rate of somatic CAG expansion and a toxic process(es) triggered by somatically expanded repeats. Thus, a comprehensive understanding of HD pathogenesis will necessitate insight into mechanisms underlying both CAG instability and cellular toxicity.…”

“…HD is caused by the inheritance of an expansion >35 repeats of a polymorphic CAG repeat tract in the HTT gene ( Macdonald et al, 1993 ), ultimately resulting in cellular dysfunction and death, with medium-spiny neurons (MSNs) of the striatum being exquisitely sensitive to this mutation ( Vonsattel et al, 1985 ). The expanded HTT CAG repeat undergoes further time-dependent, CAG length-dependent and tissue/cell-type-dependent expansion ( Wheeler et al, 1999 ; Kennedy and Shelbourne, 2000 ; Kennedy et al, 2003 ; Veitch et al, 2007 ; Gonitel et al, 2008 ; Swami et al, 2009 ; Lee et al, 2010 ; Lee et al, 2011 ; Kovalenko et al, 2012 ; Larson et al, 2015 ; Geraerts et al, 2016 ; Ament et al, 2017 ; Mouro Pinto et al, 2020 ). The repeat is highly unstable in the brain, particularly in MSNs ( Kovalenko et al, 2012 ), with individual-specific differences in the extent of somatic CAG expansion in HD postmortem brain associated with age of onset ( Swami et al, 2009 ).…”

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

“…Notably, the striatum was revealed as the region with the largest expansions in other expanded CAG•CTG repeat mouse models of DM1 [180,181], SCA1 [182] and DRPLA [183] (see also Wheeler and Dion, this issue [169]). Likewise in humans, high levels of somatic expansion are observed in striatal and/or cortical regions in individuals with other CAG•CTG repeat expansions including DM1 [184,185], SCA1 [186][187][188][189][190][191][192], SCA2 [193,194], MJD [187,190,[195][196][197], SCA7 [94,198] and DRPLA [188,195,196,[199][200][201][202][203][204]. These data suggest that regional-specific CAG•CTG repeat somatic expansion in the brain is strongly driven by major tissue-specific transacting factors.…”