Matrix Metalloproteinases Are Modifiers of Huntingtin Proteolysis and Toxicity in Huntington's Disease

Miller, John P.; Holcomb, Jennifer; Al‐Ramahi, Ismael; Haro, Maria de; Gafni, Juliette; Zhang, Ningzhe; Kim, Eugene; Sanhueza, Mario; Torcassi, Cameron; Kwak, Seung; Botas, Juan; Hughes, Robert E.; Ellerby, Lisa M.

doi:10.1016/j.neuron.2010.06.021

Cited by 153 publications

(125 citation statements)

References 60 publications

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“…A next crucial step for this area of research will be a detailed analysis of stem-cell-autonomous versus non-cell-autonomous actions in HD, as well as exploring the impact of different size aggregates for adult neurogenesis and testing compounds that have been shown to be protective to HD in rodent models to determine whether they have an impact in modulating adult neurogenesis (Miller et al 2010).…”

Section: Adult Neurogenesis In Neurodegenerative Diseasesmentioning

confidence: 99%

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

Winner¹,

Winkler

2015

Cold Spring Harb Perspect Biol

257

208

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Section: Adult Neurogenesis In Neurodegenerative Diseasesmentioning

confidence: 99%

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

Winner¹,

Winkler

2015

Cold Spring Harb Perspect Biol

257

208

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“…A recent report by the Ellerby/Hughes research team describes a similar screen for proteases capable of yielding short N-terminal fragments of Htt (41). However, there are a number of important differences in the experimental design between these two studies, explaining different (possibly complementary) findings.…”

Section: Discussionmentioning

confidence: 99%

Cysteine Proteases Bleomycin Hydrolase and Cathepsin Z Mediate N-terminal Proteolysis and Toxicity of Mutant Huntingtin

Ratovitski

Chighladze

Waldron

et al. 2011

Journal of Biological Chemistry

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N-terminal proteolysis of huntingtin is thought to be an important mediator of HD pathogenesis. The formation of short N-terminal fragments of huntingtin (cp-1/cp-2, cp-A/cp-B) has been demonstrated in cells and in vivo. We previously mapped the cp-2 cleavage site by mass spectrometry to position Arg 167 of huntingtin. The proteolytic enzymes generating short N-terminal fragments of huntingtin remain unknown. To search for such proteases, we conducted a genome-wide screen using an RNA-silencing approach and an assay for huntingtin proteolysis based on the detection of cp-1 and cp-2 fragments by Western blotting. The primary screen was carried out in HEK293 cells, and the secondary screen was carried out in neuronal HT22 cells, transfected in both cases with a construct encoding the N-terminal 511 amino acids of mutant huntingtin. For additional validation of the hits, we employed a complementary assay for proteolysis of huntingtin involving overexpression of individual proteases with huntingtin in two cell lines. The screen identified 11 enzymes, with two major candidates to carry out the cp-2 cleavage, bleomycin hydrolase (BLMH) and cathepsin Z, which are both cysteine proteases of a papain-like structure. Knockdown of either protease reduced cp-2 cleavage, and ameliorated mutant huntingtin induced toxicity, whereas their overexpression increased the cp-2 cleavage. Both proteases partially co-localized with Htt in the cytoplasm and within or in association with early and late endosomes, with some nuclear co-localization observed for cathepsin Z. BLMH and cathepsin Z are expressed in the brain and have been associated previously with neurodegeneration. Our findings further validate the cysteine protease family, and BLMH and cathepsin Z in particular, as potential novel targets for HD therapeutics.Huntington disease (HD) 3 is caused by an expansion of the CAG repeat coding for polyglutamine (polyQ) within the HD gene product huntingtin (Htt) (1, 2). It is not clear how mutant Htt causes neuronal cell death, but evidence is accumulating that N-terminal fragments of mutant Htt are important mediators of pathogenesis. N-terminal fragments of Htt are found in human postmortem brain (3-8). In cell model experiments, shorter N-terminal fragments of Htt are generally more toxic to cells than longer fragments, and mouse HD models expressing shorter fragments usually develop more severe pathology than the full-length Htt models (6, 9 -19). The proteolytic pathway for mutant Htt may include several cleavage events mediated by different enzymes involved in the generation of toxic fragments of various lengths. These enzymes may represent potential novel therapeutic targets for HD.One example of such an enzyme is caspase-6, which cleaves mutant Htt at residue 586 from its N terminus and generates a toxic fragment; YAC128 mice expressing Htt with an altered caspase-6 site have a substantially ameliorated HD phenotype (20), whereas transgenic mice expressing a caspase-6 fragment with an expanded polyQ repeat develop an HD phe...

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“…Htt can be cleaved by several caspases such as caspase 3 at positions 513 and 552 aa [84,85], caspase 2 at 552 aa [86] and by caspase 6 at 586 aa [85]. The matrix metalloproteinase MMP-10 cleaves the Htt protein at 402 aa and is active in mice with HD [87]. The presence of the Htt fragments, where the cleavage sites have been mutated, promote lower toxicity of Htt indicating that proteolytic processing of Htt could contribute to HD pathogenesis [84,88,89].…”

Section: Proteolysis In Huntington's Disease (Hd)mentioning

confidence: 99%