Analysis of LINE1 Retrotransposons in Huntington’s Disease

Transposable elements (TEs) are mobile genetic elements that made up about half the human genome. Among them, the autonomous non-LTR retrotransposon long interspersed nuclear element-1 (L1) is the only currently active TE in mammals and covers about 17% of the mammalian genome. L1s exert their function as structural elements in the genome, as transcribed RNAs to influence chromatin structure and as retrotransposed elements to shape genomic variation in somatic cells. L1s activity has been shown altered in several diseases of the nervous system. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by an expansion of a CAG repeat in the HTT gene which leads to a gradual loss of neurons most prominently in the striatum and, to a lesser extent, in cortical brain regions. The length of the expanded CAG tract is related to age at disease onset, with longer repeats leading to earlier onset. Here we carried out bioinformatic analysis of public RNA-seq data of a panel of HD mouse models showing that a decrease of L1 RNA expression recapitulates two hallmarks of the disease: it correlates to CAG repeat length and it occurs in the striatum, the site of neurodegeneration. Results were then experimentally validated in HttQ111 knock-in mice. The expression of L1-encoded proteins was independent from L1 RNA levels and differentially regulated in time and tissues. The pattern of expression L1 RNAs in human HD post-mortem brains showed similarity to mouse models of the disease. This work suggests the need for further study of L1s in HD and adds support to the current hypothesis that dysregulation of TEs may be involved in neurodegenerative diseases.

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Extensive Expression Analysis of Htt Transcripts in Brain Regions from the zQ175 HD Mouse Model Using a QuantiGene Multiplex Assay

Scientific Reports ◽

10.1038/s41598-019-52411-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Aikaterini S. Papadopoulou ◽

Casandra Gomez-Paredes ◽

Michael A. Mason ◽

Bridget A. Taxy ◽

David Howland ◽

...

Keyword(s):

Mouse Model ◽

Neurodegenerative Disorder ◽

Simultaneous Detection ◽

Brain Regions ◽

Cag Repeat ◽

Highly Pathogenic ◽

Exon 2 ◽

Mouse Tissues ◽

Exon 1 ◽

The Brain

Abstract Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of the huntingtin (HTT) gene. HTT mRNA contains 67 exons and does not always splice between exon 1 and exon 2 leading to the production of a small polyadenylated HTTexon1 transcript, and the full-length HTT mRNA has three 3′UTR isoforms. We have developed a QuantiGene multiplex panel for the simultaneous detection of all of these mouse Htt transcripts directly from tissue lysates and demonstrate that this can replace the more work-intensive Taqman qPCR assays. We have applied this to the analysis of brain regions from the zQ175 HD mouse model and wild type littermates at two months of age. We show that the incomplete splicing of Htt occurs throughout the brain and confirm that this originates from the mutant and not endogenous Htt allele. Given that HTTexon1 encodes the highly pathogenic exon 1 HTT protein, it is essential that the levels of all Htt transcripts can be monitored when evaluating HTT lowering approaches. Our QuantiGene panel will allow the rapid comparative assessment of all Htt transcripts in cell lysates and mouse tissues without the need to first extract RNA.

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Striatal Circuit Development and Its Alterations in Huntington’s Disease

10.20944/preprints202005.0488.v1 ◽

2020 ◽

Author(s):

Margaux Lebouc ◽

Quentin Richard ◽

Maurice Garret ◽

Jérôme Baufreton

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Mouse Models ◽

Neurodegenerative Disorder ◽

Repeat Expansion ◽

Cag Repeat ◽

Rodent Models ◽

Network Development ◽

Cag Repeat Expansion ◽

Circuit Development

Huntington's disease (HD) is an inherited neurodegenerative disorder that usually starts during midlife with progressive alterations of motor and cognitive functions. The disease is caused by a CAG repeat expansion within the huntingtin gene leading to severe striatal neurodegeneration. Recent studies conducted on pre-HD children highlight early striatal developmental alterations starting as soon as 6 years old, the earliest age assessed. These findings, in line with data from mouse models of HD, raise the question of when during development do the first disease-related striatal alterations emerge or whether they contribute to the later appearance of the neurodegenerative features of the disease. In this review we will describe the different stages of striatal network development and then discuss recent evidence for its alterations in rodent models of the disease. We argue that a better understanding of the striatum’s development should help in assessing aberrant neurodevelopmental processes linked to the HD mutation.

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Identification and drug-induced reversion of molecular signatures of Alzheimer’s disease onset and progression in AppNL-G-F, AppNL-F and 3xTg-AD mouse models

10.1101/2021.03.17.435753 ◽

2021 ◽

Author(s):

Eduardo Pauls ◽

Sergi Bayod ◽

Lídia Mateo ◽

Víctor Alcalde ◽

Teresa Juan-Blanco ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mouse Models ◽

Neurodegenerative Disorder ◽

Disease Onset ◽

Protein Quantification ◽

Clear Correlation ◽

Gene And Protein Expression

AbstractAlzheimer’s disease (AD) is the most common form of dementia. Over fifty years of intense research have revealed many key elements of the biology of this neurodegenerative disorder. However, our understanding of the molecular bases of the disease is still incomplete, and the medical treatments available for AD are mainly symptomatic and hardly effective. Indeed, the robustness of biological systems has revealed that the modulation of a single target is unlikely to yield the desired outcome and we should therefore move from gene-centric to systemic therapeutic strategies. Here we present the complete characterization of three murine models of AD at different stages of the disease (i.e. onset, progression and advanced). To identify genotype-to-phenotype relationships, we combine the cognitive assessment of these mice with histological analyses and full transcriptional and protein quantification profiling of the hippocampus. Comparison of the gene and protein expression trends observed in AD progression and physiological aging revealed certain commonalities, such as the upregulation of microglial and inflammation markers. However, although AD models show accelerated aging, other factors specifically associated with Aβ pathology are involved. Despite the clear correlation between mRNA and protein levels of the dysregulated genes, we discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable. Indeed, we show that at least two of these proteins, namely lfit3 and Syt11, co-localize with Aβ plaques in the brain. Finally, we derived specific Aβ-related molecular AD signatures and looked for drugs able to globally revert them. We found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.TeaserThe comprehensive characterization of three AD mouse models reveals disease signatures that we used to identify approved drugs able to modify the etiology of the pathology and overturn cognitive impairment.

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Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation

Journal of Huntington s Disease ◽

10.3233/jhd-200433 ◽

2021 ◽

Vol 10 (1) ◽

pp. 53-74

Author(s):

Marc Ciosi ◽

Sarah A. Cumming ◽

Afroditi Chatzi ◽

Eloise Larson ◽

William Tottey ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Disease Onset ◽

Somatic Mosaicism ◽

Genotyping By Sequencing ◽

Repeat Length ◽

Cag Repeat ◽

Length Variation ◽

Allele Size ◽

Pcr Products ◽

Alternative Approaches

Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of the HTT CAG repeat. Affected individuals inherit ≥36 repeats and longer alleles cause earlier onset, greater disease severity and faster disease progression. The HTT CAG repeat is genetically unstable in the soma in a process that preferentially generates somatic expansions, the proportion of which is associated with disease onset, severity and progression. Somatic mosaicism of the HTT CAG repeat has traditionally been assessed by semi-quantitative PCR-electrophoresis approaches that have limitations (e.g., no information about sequence variants). Genotyping-by-sequencing could allow for some of these limitations to be overcome. Objective: To investigate the utility of PCR sequencing to genotype large (>50 CAGs) HD alleles and to quantify the associated somatic mosaicism. Methods: We have applied MiSeq and PacBio sequencing to PCR products of the HTT CAG repeat in transgenic R6/2 mice carrying ∼55, ∼110, ∼255 and ∼470 CAGs. For each of these alleles, we compared the repeat length distributions generated for different tissues at two ages. Results: We were able to sequence the CAG repeat full length in all samples. However, the repeat length distributions for samples with ∼470 CAGs were biased towards shorter repeat lengths. Conclusion: PCR sequencing can be used to sequence all the HD alleles considered, but this approach cannot be used to estimate modal allele size or quantify somatic expansions for alleles ⪢250 CAGs. We review the limitations of PCR sequencing and alternative approaches that may allow the quantification of somatic contractions and very large somatic expansions.

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Nuclear and Mitochondrial Genome, Epigenome and Gut Microbiome: Emerging Molecular Biomarkers for Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22189839 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9839

Author(s):

Gleyce Fonseca Cabral ◽

Ana Paula Schaan ◽

Giovanna C. Cavalcante ◽

Camille Sena-dos-Santos ◽

Tatiane Piedade de Souza ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Genome ◽

Gut Microbiome ◽

Neurodegenerative Disorder ◽

Disease Onset ◽

Clinical Signs ◽

Genomic Variation ◽

Increasing Demand ◽

Based Medicine

Background: Parkinson’s disease (PD) is currently the second most common neurodegenerative disorder, burdening about 10 million elderly individuals worldwide. The multifactorial nature of PD poses a difficult obstacle for understanding the mechanisms involved in its onset and progression. Currently, diagnosis depends on the appearance of clinical signs, some of which are shared among various neurologic disorders, hindering early diagnosis. There are no effective tools to prevent PD onset, detect the disease in early stages or accurately report the risk of disease progression. Hence, there is an increasing demand for biomarkers that may identify disease onset and progression, as treatment-based medicine may not be the best approach for PD. Over the last few decades, the search for molecular markers to predict susceptibility, aid in accurate diagnosis and evaluate the progress of PD have intensified, but strategies aimed to improve individualized patient care have not yet been established. Conclusions: Genomic variation, regulation by epigenomic mechanisms, as well as the influence of the host gut microbiome seem to have a crucial role in the onset and progress of PD, thus are considered potential biomarkers. As such, the human nuclear and mitochondrial genome, epigenome, and the host gut microbiome might be the key elements to the rise of personalized medicine for PD patients.

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Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington’s Disease

Journal of Huntington s Disease ◽

10.3233/jhd-200423 ◽

2021 ◽

Vol 10 (1) ◽

pp. 149-163

Author(s):

Xiaonan Zhao ◽

Daman Kumari ◽

Carson J. Miller ◽

Geum-Yi Kim ◽

Bruce Hayward ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Mouse Models ◽

Fragile X ◽

Friedreich Ataxia ◽

Disease Onset ◽

Neuronal Cell ◽

Repeat Expansion ◽

Cag Repeat ◽

Dna Repeats

Huntington’s disease (HD) is one of a large group of human disorders that are caused by expanded DNA repeats. These repeat expansion disorders can have repeat units of different size and sequence that can be located in any part of the gene and, while the pathological consequences of the expansion can differ widely, there is evidence to suggest that the underlying mutational mechanism may be similar. In the case of HD, the expanded repeat unit is a CAG trinucleotide located in exon 1 of the huntingtin (HTT) gene, resulting in an expanded polyglutamine tract in the huntingtin protein. Expansion results in neuronal cell death, particularly in the striatum. Emerging evidence suggests that somatic CAG expansion, specifically expansion occurring in the brain during the lifetime of an individual, contributes to an earlier disease onset and increased severity. In this review we will discuss mouse models of two non-CAG repeat expansion diseases, specifically the Fragile X-related disorders (FXDs) and Friedreich ataxia (FRDA). We will compare and contrast these models with mouse and patient-derived cell models of various other repeat expansion disorders and the relevance of these findings for somatic expansion in HD. We will also describe additional genetic factors and pathways that modify somatic expansion in the FXD mouse model for which no comparable data yet exists in HD mice or humans. These additional factors expand the potential druggable space for diseases like HD where somatic expansion is a significant contributor to disease impact.

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Cerebral Vitamin B5 (D-Pantothenic Acid) Deficiency as a Potential Cause of Metabolic Perturbation and Neurodegeneration in Huntington’s Disease

Metabolites ◽

10.3390/metabo9060113 ◽

2019 ◽

Vol 9 (6) ◽

pp. 113 ◽

Cited By ~ 7

Author(s):

Stefano Patassini ◽

Paul Begley ◽

Jingshu Xu ◽

Stephanie Church ◽

Nina Kureishy ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Tricarboxylic Acid Cycle ◽

Pantothenic Acid ◽

Polyol Pathway ◽

Brain Regions ◽

Cag Repeat ◽

Projection Neurons ◽

Vitamin B5

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the HTT gene. HD usually manifests in mid-life with loss of GABAergic projection neurons from the striatum accompanied by progressive atrophy of the putamen followed by other brain regions, but linkages between the genetics and neurodegeneration are not understood. We measured metabolic perturbations in HD-human brain in a case-control study, identifying pervasive lowering of vitamin B5, the obligatory precursor of coenzyme A (CoA) that is essential for normal intermediary metabolism. Cerebral pantothenate deficiency is a newly-identified metabolic defect in human HD that could potentially: (i) impair neuronal CoA biosynthesis; (ii) stimulate polyol-pathway activity; (iii) impair glycolysis and tricarboxylic acid cycle activity; and (iv) modify brain-urea metabolism. Pantothenate deficiency could lead to neurodegeneration/dementia in HD that might be preventable by treatment with vitamin B5.

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Transcriptional correlates of the pathological phenotype in a Huntington’s disease mouse model

Scientific Reports ◽

10.1038/s41598-019-55177-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Andrea Gallardo-Orihuela ◽

Irati Hervás-Corpión ◽

Carmen Hierro-Bujalance ◽

Daniel Sanchez-Sotano ◽

Gema Jiménez-Gómez ◽

...

Keyword(s):

Mouse Models ◽

Neuronal Development ◽

Neurodegenerative Disorder ◽

Disease Onset ◽

Cag Repeats ◽

Brain Areas ◽

Transcriptional Dysregulation ◽

Transcriptional Alterations ◽

Exon 1 ◽

The Brain

AbstractHuntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. Although a negative correlation between the number of CAG repeats and the age of disease onset is established, additional factors may contribute to the high heterogeneity of the complex manifestation of symptoms among patients. This variability is also observed in mouse models, even under controlled genetic and environmental conditions. To better understand this phenomenon, we analysed the R6/1 strain in search of potential correlates between pathological motor/cognitive phenotypical traits and transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated across the examined brain areas (the prefrontal cortex, striatum, hippocampus and cerebellum), exhibited tissue-specific correlations with particular phenotypical traits that were attributable to the contribution of the brain region to that trait (e.g., striatum and rotarod performance, cerebellum and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation associated with HD was partially exacerbated in mice that showed poor overall phenotypical scores, especially in genes with relevant roles in striatal functioning (e.g., Pde10a, Drd1, Drd2, Ppp1r1b). However, we also observed transcripts associated with relatively better outcomes, such as Nfya (CCAAT-binding transcription factor NF-Y subunit A) plus others related to neuronal development, apoptosis and differentiation. In this study, we demonstrated that altered brain transcription can be related to the manifestation of HD-like symptoms in mouse models and that this can be extrapolated to the highly heterogeneous population of HD patients.

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Hippocampal Neurogenesis, Cognitive Deficits and Affective Disorder in Huntington's Disease

Neural Plasticity ◽

10.1155/2012/874387 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 28

Author(s):

Mark I. Ransome ◽

Thibault Renoir ◽

Anthony J. Hannan

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Mouse Models ◽

Adult Neurogenesis ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Brain Regions ◽

Transgenic Animal ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis

Huntington’s disease (HD) is a neurodegenerative disorder caused by a tandem repeat expansion encoding a polyglutamine tract in the huntingtin protein. HD involves progressive psychiatric, cognitive, and motor symptoms, the selective pathogenesis of which remains to be mechanistically elucidated. There are a range of different brain regions, including the cerebral cortex and striatum, known to be affected in HD, with evidence for hippocampal dysfunction accumulating in recent years. In this review we will focus on hippocampal abnormalities, in particular, deficits of adult neurogenesis. We will discuss potential molecular mechanisms mediating disrupted hippocampal neurogenesis, and how this deficit of cellular plasticity may in turn contribute to specific cognitive and affective symptoms that are prominent in HD. The generation of transgenic animal models of HD has greatly facilitated our understanding of disease mechanisms at molecular, cellular, and systems levels. Transgenic HD mice have been found to show progressive behavioral changes, including affective, cognitive, and motor abnormalities. The discovery, in multiple transgenic lines of HD mice, that adult hippocampal neurogenesis and synaptic plasticity is disrupted, may help explain specific aspects of cognitive and affective dysfunction. Furthermore, these mouse models have provided insight into potential molecular mediators of adult neurogenesis deficits, such as disrupted serotonergic and neurotrophin signaling. Finally, a number of environmental and pharmacological interventions which are known to enhance adult hippocampal neurogenesis have been found to have beneficial affective and cognitive effects in mouse models, suggesting common molecular targets which may have therapeutic utility for HD and related diseases.

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Molecular diagnosis of Huntington disease in Brazilian patients

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2000000100002 ◽

2000 ◽

Vol 58 (1) ◽

pp. 11-17 ◽

Cited By ~ 12

Author(s):

TEREZA C. LIMA E SILVA ◽

HELIANE GUERRA SERRA ◽

CARMEN S. BERTUZZO ◽

ISCIA LOPES-CENDES

Keyword(s):

Molecular Diagnosis ◽

Huntington Disease ◽

Neurodegenerative Disorder ◽

Age At Onset ◽

Disease Onset ◽

Significant Negative Correlation ◽

Cag Repeat ◽

Cag Repeats ◽

Unrelated Control ◽

Intermediate Size

Huntington disease (HD) is a progressive neurodegenerative disorder with autosomal dominant inheritance, characterized by choreiform movements and cognitive impairment. Onset of symptoms is around 40 years of age and progression to death occurs in approximately 10 to 15 years from the time of disease onset. HD is associated with an unstable CAG repeat expansion at the 5' and of the IT15 gene. We have genotyped the CAG repeat in the IT15 gene in 44 Brazilian individuals (42 patients and 2 unaffected family members) belonging to 34 unrelated families thought to segregate HD. We found one expanded CAG allele in 32 individuals (76%) belonging to 25 unrelated families. In these HD patients, expanded alleles varied from 43 to 73 CAG units and normal alleles varied from 18 to 26 CAGs. A significant negative correlation between age at onset of symptoms and size of the expanded CAG allele was found (r=0.6; p=0.0001); however, the size of the expanded CAG repeat could explain only about 40% of the variability in age at onset (r2=0.4). In addition, we genotyped 25 unrelated control individuals (total of 50 alleles) and found normal CAG repeats varying from 16 to 33 units. The percentage of heterozigocity of the normal allele in the control population was 88%. In conclusion, our results showed that not all patients with the "HD" phenotype carried the expansion at the IT15 gene. Furthermore, molecular diagnosis was possible in all individuals, since no alleles of intermediate size were found. Therefore, molecular confirmation of the clinical diagnosis in HD should be sought in all suspected patients, making it possible for adequate genetic counseling.

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