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Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase.

ABSTRACT: There is no treatment for the neurodegenerative disorder Huntington disease (HD). Cystamine is a candidate drug; however, the mechanisms by which it operates remain unclear. We show here that cystamine increases levels of the heat shock DnaJ-containing protein 1b (HSJ1b) that are low in HD patients. HSJ1b inhibits polyQ-huntingtin-induced death of striatal neurons and neuronal dysfunction in Caenorhabditis elegans. This neuroprotective effect involves stimulation of the secretory pathway through formation of clathrin-coated vesicles containing brain-derived neurotrophic factor (BDNF). Cystamine increases BDNF secretion from the Golgi region that is blocked by reducing HSJ1b levels or by overexpressing transglutaminase. We demonstrate that cysteamine, the FDA-approved reduced form of cystamine, is neuroprotective in HD mice by increasing BDNF levels in brain. Finally, cysteamine increases serum levels of BDNF in mouse and primate models of HD. Therefore, cysteamine is a potential treatment for HD, and serum BDNF levels can be used as a biomarker for drug efficacy.

SUBMITTER: Borrell-Pages M

PROVIDER: S-EPMC1430359 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase.

Borrell-Pagès Maria M Canals Josep M JM Cordelières Fabrice P FP Parker J Alex JA Pineda José R JR Grange Ghislaine G Bryson Elzbieta A EA Guillermier Martine M Hirsch Etienne E Hantraye Philippe P Cheetham Michael E ME Néri Christian C Alberch Jordi J Brouillet Emmanuel E Saudou Frédéric F Humbert Sandrine S

The Journal of clinical investigation 20060406 5

There is no treatment for the neurodegenerative disorder Huntington disease (HD). Cystamine is a candidate drug; however, the mechanisms by which it operates remain unclear. We show here that cystamine increases levels of the heat shock DnaJ-containing protein 1b (HSJ1b) that are low in HD patients. HSJ1b inhibits polyQ-huntingtin-induced death of striatal neurons and neuronal dysfunction in Caenorhabditis elegans. This neuroprotective effect involves stimulation of the secretory pathway through ...[more]

PMID: 16604191

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Project description:Huntington Disease (HD) is a dominantly inherited, relentlessly progressive neurodegenerative disease. Caused by a polyglutamine expansion in the mutant huntingtin protein (mhtt), HD pathogenesis impairs function in the cerebral cortex and in medium spiny neurons of the striatum and involves transcriptional dysregulation of a number of genes. Of these genes, silencing of genes related to mitochondrial function is believed to explain metabolic dysfunction in rodent models of HD. Here we show that transglutaminase 2 (TG2), which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes. TG2 inhibition by RNA knockdown, genetic deletion, or administration of a novel irreversible, peptide-based TG2 inhibitor (ZDON) de-repressed two established regulators of mitochondrial function, PGC-1? and cytochrome c in a cell model of HD. TG2 must localize to non-coding or coding regions of these mitochondrial metabolic genes to silence their transcription. As expected, TG2 inhibition reversed the increased susceptibility of HD mouse cells and human HD myoblasts to the mitochondrial toxin, 3-nitroproprionic acid (3-NP); however, protection mediated by TG2 inhibition was not associated with improved mitochondrial bioenergetics. Indeed, an unbiased array analysis indicated that TG2 inhibition leads to normalization of not only mitochondrial genes but of nearly 40% of genes that are dysregulated in HD mouse striatal neurons, including chaperone and histone genes. Indeed, TG2 interacts directly with Histone 3 in the nucleus. Moreover, TG2 inhibition significantly attenuated photoreceptor degeneration in a Drosophila model of HD and protected mouse HD striatal neurons (YAC128) from NMDA- induced toxicity. Altogether these findings demonstrate that TG2 mediates its deleterious effects in HD by contributing to broad transcriptional dysregulation of genes representing many cellular functions. These studies define a novel HDAC-independent epigenetic strategy for treating neurodegeneration. To evaluate the effect of TG2 inhibition (treatment with ZDON, Boc-DON, CystamineA, and Control) in striatal cell lines from a transgenic model of Huntington disease (Q111) vs. control (Q7). One sample (WT.boc.3, 4068264015_G) failed the QC test and was excluded from further analyses.

Project description:Huntington Disease (HD) is a dominantly inherited, relentlessly progressive neurodegenerative disease. Caused by a polyglutamine expansion in the mutant huntingtin protein (mhtt), HD pathogenesis impairs function in the cerebral cortex and in medium spiny neurons of the striatum and involves transcriptional dysregulation of a number of genes. Of these genes, silencing of genes related to mitochondrial function is believed to explain metabolic dysfunction in rodent models of HD. Here we show that transglutaminase 2 (TG2), which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes. TG2 inhibition by RNA knockdown, genetic deletion, or administration of a novel irreversible, peptide-based TG2 inhibitor (ZDON) de-repressed two established regulators of mitochondrial function, PGC-1α and cytochrome c in a cell model of HD. TG2 must localize to non-coding or coding regions of these mitochondrial metabolic genes to silence their transcription. As expected, TG2 inhibition reversed the increased susceptibility of HD mouse cells and human HD myoblasts to the mitochondrial toxin, 3-nitroproprionic acid (3-NP); however, protection mediated by TG2 inhibition was not associated with improved mitochondrial bioenergetics. Indeed, an unbiased array analysis indicated that TG2 inhibition leads to normalization of not only mitochondrial genes but of nearly 40% of genes that are dysregulated in HD mouse striatal neurons, including chaperone and histone genes. Indeed, TG2 interacts directly with Histone 3 in the nucleus. Moreover, TG2 inhibition significantly attenuated photoreceptor degeneration in a Drosophila model of HD and protected mouse HD striatal neurons (YAC128) from NMDA- induced toxicity. Altogether these findings demonstrate that TG2 mediates its deleterious effects in HD by contributing to broad transcriptional dysregulation of genes representing many cellular functions. These studies define a novel HDAC-independent epigenetic strategy for treating neurodegeneration.

Project description:Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Therapeutics that lower HTT have shown preclinical promise and are being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. We have reported that mutant HTT (mHTT) in the CSF of HD patients correlates with clinical measures, including disease burden as well as motor and cognitive performance. We have also shown that lowering HTT in the brains of HD mice results in correlative reduction of mHTT in the CSF, prompting the use of this measure as an exploratory marker of target engagement in clinical trials. In this study, we investigate the mechanisms of mHTT clearance from the brain in adult mice of both sexes to elucidate the significance of therapy-induced CSF mHTT changes. We demonstrate that, although neurodegeneration increases CSF mHTT concentrations, mHTT is also present in the CSF of mice in the absence of neurodegeneration. Importantly, we show that secretion of mHTT from cells in the CNS followed by glymphatic clearance from the extracellular space contributes to mHTT in the CSF. Furthermore, we observe secretion of wild type HTT from healthy control neurons, suggesting that HTT secretion is a normal process occurring in the absence of pathogenesis. Overall, our data support both passive release and active clearance of mHTT into CSF, suggesting that its treatment-induced changes may represent a combination of target engagement and preservation of neurons.SIGNIFICANCE STATEMENT: Changes in CSF mutant huntingtin (mHTT) are being used as an exploratory endpoint in HTT lowering clinical trials for the treatment of Huntington disease (HD). Recently, it was demonstrated that intrathecal administration of a HTT lowering agent leads to dose-dependent reduction of CSF mHTT in HD patients. However, little is known about how HTT, an intracellular protein, reaches the extracellular space and ultimately the CSF. Our findings that HTT enters CSF by both passive release and active secretion followed by glymphatic clearance may have significant implications for interpretation of treatment-induced changes of CSF mHTT in clinical trials for HD.

Project description:Background:Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Methods:Brain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Results:Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. Conclusions:This study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide.

Dataset Information

Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase.

Publications

Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase.

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