Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo

O’Brien, Robert; DeGiacomo, Francesco; Holcomb, Jennifer; Bonner, Akilah; Ring, Karen; Zhang, Ningzhe; Zafar, Khan Shoeb; Weiss, Andreas; Lager, Brenda; Schilling, Birgit; Gibson, Bradford W.; Chen, Sylvia; Kwak, Seung; Ellerby, Lisa M.

doi:10.1074/jbc.m114.623561

Cited by 21 publications

(19 citation statements)

References 79 publications

(65 reference statements)

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“…Furthermore, neurodegeneration, locomotor deficits and production of mHtt586 fragments are unaffected by Casp6 ablation in HD mice [33,34,48], suggesting that mHtt cleavage at D586 residue is not specific to Casp6 in vivo and that Casp6 activity is not required for the pathogenic aspects of mHtt. Moreover, other caspases generate mHtt cleaved at D586 [23,33,34], and shorter Casp2-generated N-terminal Htt fragments are significantly more toxic than Casp6-generated fragments in mice [49]. These and our results indicate that in the absence of mHtt, Casp6 is not detrimental to MSN and striatal tissues.…”

Section: Discussionsupporting

confidence: 61%

Differential susceptibility of striatal, hippocampal and cortical neurons to Caspase-6

et al. 2018

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Active cysteinyl protease Caspase-6 is associated with early Alzheimer and Huntington diseases. Higher entorhinal cortex and hippocampal Caspase-6 levels correlate with lower cognitive performance in aged humans. Caspase-6 induces axonal degeneration in human primary neuron cultures and causes inflammation and neurodegeneration in mouse hippocampus, and age-dependent memory impairment. To assess whether Caspase-6 causes damage to another neuronal system, a transgenic knock-in mouse overexpressing a self-activated form of Caspase-6 five-fold in the striatum, the area affected in Huntington disease, and 2.5-fold in the hippocampus and cortex, was generated. Detection of Tubulin cleaved by Caspase-6 confirmed Caspase-6 activity. The Caspase-6 expressing mice and control littermates were subjected to behavioral tests to assess Huntington disease-relevant psychiatric, motor, and cognitive deficits. Depression was excluded with the forced swim and sucrose consumption tests. Motor deficits were absent in the nesting, clasping, rotarod, vertical pole, gait, and open field analyzes. However, Caspase-6 mice developed age-dependent episodic and spatial memory deficits identified by novel object recognition, Barnes maze and Morris water maze assays. Neuron numbers were maintained in the striatum, hippocampus, and cortex. Microglia and astrocytes were increased in the hippocampal stratum lacunosum molecular and in the cortex, but not in the striatum. Synaptic mRNA profiling identified two differentially expressed genes in transgenic hippocampus, but none in striatum. Caspase-6 impaired synaptic transmission and induced neurodegeneration in hippocampal CA1 neurons, but not in striatal medium spiny neurons. These data revealed that active Caspase-6 in the striatal medium spiny neurons failed to induce inflammation, neurodegeneration or behavioral abnormalities, whereas active Caspase-6 in the cortex and hippocampus impaired episodic and spatial memories, and induced inflammation, neuronal dysfunction, and neurodegeneration. The results indicate age and neuronal subtype-dependent Caspase-6 toxicity and highlight the importance of targeting the correct neuronal subtype to identify underlying molecular mechanisms of neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 61%

Differential susceptibility of striatal, hippocampal and cortical neurons to Caspase-6

et al. 2018

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“…While additional work will be required to sort out the contributions of HD-RAN proteins in disease, two mouse models that show HD-like phenotypes were developed using a mixed CAG/CAA repeat encoding a polyGln tract (Gray et al, 2008; O’Brien et al, 2015). While these animals express a polyGln expansion across the CAG/CAA repeat, the CAG/CAA mixed repeat is also predicted to form a complex hairpin-containing structure that may also produce two novel di-peptide (Thr/Ala and Asn/Ser) RAN proteins, which may contribute to the phenotypes found in these models.…”

Section: Discussionmentioning

confidence: 99%

RAN Translation in Huntington Disease

Báñez-Coronel

Ayhan

Tarabochia

et al. 2015

Neuron

300

337

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SUMMARY Huntington disease (HD) is caused by a CAG·CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other poly-glutamine diseases.

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“…In this report, we use a well-validated Drosophila model of HD to ask whether expanded polyQ is intrinsically toxic and to identify possible sources of intrinsic and/or extrinsic modifiers of HTT toxicity. In this model, transgenic human HTT does not undergo proteolytic processing or splicing aberrations (18), the genetic background can be controlled, and transgenes can be inserted into a defined chromosomal location to avoid integration-site differences (19). These advantages provide an excellent platform for comparing the pathogenic properties and cellular behavior (i.e.…”

Section: Introductionmentioning

confidence: 99%

Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT

Chongtham

Bornemann

Barbaro

et al. 2020

Human Molecular Genetics

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Huntington’s disease (HD) is caused by an expansion of a poly glutamine (polyQ) stretch in the huntingtin protein (HTT) that is necessary to cause pathology and formation of HTT aggregates. Here we ask whether expanded polyQ is sufficient to cause pathology and aggregate formation. By addressing the sufficiency question, one can identify cellular processes and structural parameters that influence HD pathology and HTT subcellular behavior (i.e. aggregation state and subcellular location). Using Drosophila, we compare the effects of expressing mutant full-length human HTT (fl-mHTT) to the effects of mutant human HTTexon1 and to two commonly used synthetic fragments, HTT171 and shortstop (HTT118). Expanded polyQ alone is not sufficient to cause inclusion formation since full-length HTT and HTTex1 with expanded polyQ are both toxic although full-length HTT remains diffuse while HTTex1 forms inclusions. Further, inclusions are not sufficient to cause pathology since HTT171-120Q forms inclusions but is benign and co-expression of HTT171-120Q with non-aggregating pathogenic fl-mHTT recruits fl-mHTT to aggregates and rescues its pathogenicity. Additionally, the influence of sequences outside the expanded polyQ domain is revealed by finding that small modifications to the HTT118 or HTT171 fragments can dramatically alter their subcellular behavior and pathogenicity. Finally, mutant HTT subcellular behavior is strongly modified by different cell and tissue environments (e.g. fl-mHTT appears as diffuse nuclear in one tissue and diffuse cytoplasmic in another but toxic in both). These observations underscore the importance of cellular and structural context for the interpretation and comparison of experiments using different fragments and tissues to report the effects of expanded polyQ.

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Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo

Cited by 21 publications

References 79 publications

Differential susceptibility of striatal, hippocampal and cortical neurons to Caspase-6

Differential susceptibility of striatal, hippocampal and cortical neurons to Caspase-6

RAN Translation in Huntington Disease

Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT

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