Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

She, Angela; Kurtser, Iren; Reis, Surya A.; Hennig, Krista M.; Lai, Jenny; Lang, Audrey; Zhao, Wenqian; Mazitschek, Ralph; Dickerson, Bradford C.; Herz, Joachim; Haggarty, Stephen J.

doi:10.1016/j.chembiol.2017.06.010

Cited by 36 publications

(52 citation statements)

References 42 publications

(64 reference statements)

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“…Using neuroimaging tools designed to measure the distribution of epigenetic enzymes, we can now begin to explore the relationships among the amount and location of enzymes, brain anatomy and function, and disease phenotypes. Of the epigenetic enzymes that can regulate gene transcription and influence behavior, histone deacetylases (HDACs) have emerged as potential targets for therapeutic interventions (5)(6)(7)(8). In the healthy brain normal HDAC activity is critical for maintenance of neural cell identity, survival, and the activity-dependent regulation of neuroplasticity (2,(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Gilbert¹,

Zürcher²,

Wu³

et al. 2018

Journal of Clinical Investigation

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BACKGROUND.Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [ 11 C]Martinostat positron emission tomography (PET). METHODS.In a case-control study, relative [ 11 C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered. RESULTS.Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls.CONCLUSIONS. These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans.The severity of cognitive deficits strongly impacts functional outcomes including quality of life (45,46). Thus, amelioration of this highly debilitating form of cognitive impairment represents an important unmet need for SCZ treatment (46).We find that patients with SCZ/schizoaffective disorder (SAD) show differential [ 11 C]Martinostat brain uptake patterns compared with healthy controls, and regional [ 11 C]Martinostat brain uptake correlates with cognitive performance scores.

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Section: Introductionmentioning

confidence: 99%

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Gilbert¹,

Zürcher²,

Wu³

et al. 2018

Journal of Clinical Investigation

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“…The human GRN promoter has been well characterized ( Figure S3 A), 26 and its activity is associated with epigenetic modifications. 27 , 28 , 29 We designed four gRNAs complementary to the GRN promoter ( Figure 2 E; Figures S3 B and S3C). The dCas9 epi-suppressors and gRNAs were co-transfected into 293T cells.…”

Section: Resultsmentioning

confidence: 99%

“… 30 , 31 In addition, the promoter activity is associated with epigenetic mutations, including increased DNA methylation in patients with sporadic FTLD 27 , 28 and altered histone acetylation. 29 …”

Section: Discussionmentioning

confidence: 99%

Epigenetic Targeting of Granulin in Hepatoma Cells by Synthetic CRISPR dCas9 Epi-suppressors

Wang

Guo

et al. 2018

Molecular Therapy - Nucleic Acids

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The CRISPR-associated Cas9 system can modulate disease-causing alleles both in vivo and ex vivo, raising the possibility of therapeutic genome editing. In addition to gene targeting, epigenetic modulation by the catalytically inactive dCas9 may also be a potential form of cancer therapy. Granulin (GRN), a potent pluripotent mitogen and growth factor that promotes cancer progression by maintaining self-renewal of hepatic stem cancer cells, is upregulated in hepatoma tissues and is associated with decreased tumor survival in patients with hepatoma. We synthesized a group of dCas9 epi-suppressors to target GRN by tethering the C terminus of dCas9 with three epigenetic suppressor genes: DNMT3a (DNA methyltransferase), EZH2 (histone 3 lysine 27 methyltransferase), and KRAB (the Krüppel-associated box transcriptional repression domain). In conjunction with guide RNAs (gRNAs), the dCas9 epi-suppressors caused significant decreases in GRN mRNA abundance in Hep3B hepatoma cells. These dCas9 epi-suppressors initiated de novo CpG DNA methylation in the GRN promoter, and they produced histone codes that favor gene suppression, including decreased H3K4 methylation, increased H3K9 methylation, and enhanced HP1a binding. Epigenetic knockdown of GRN led to the inhibition of cell proliferation, decreased tumor sphere formation, and reduced cell invasion. These changes were achieved at least partially through the MMP/TIMP pathway. This study thus demonstrates the potential utility of using dCas9 epi-suppressors in the development of epigenetic targeting against tumors.

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“…The lentiviral delivery of progranulin to degenerating brain regions protects against neurotoxicity and cognitive defects in mouse models of Parkinson's disease [60] and Alzheimer's disease [61]. As such, efforts to increase progranulin production in patients are underway [62][63][64][65]. However, a more recent study has suggested that progranulin delivery to brain promotes in T-cell infiltration and neuronal and glial degeneration [66].…”

Section: Discussionmentioning

confidence: 99%

Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response

et al. 2019

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The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age-and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.

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Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

Cited by 36 publications

References 42 publications

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Epigenetic Targeting of Granulin in Hepatoma Cells by Synthetic CRISPR dCas9 Epi-suppressors

Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response

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