Publications by authors named "Emad A Chishti"

3 Publications

  • Page 1 of 1

Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology.

Aging Cell 2021 07 12;20(7):e13416. Epub 2021 Jun 12.

Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA.

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer's disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the treatment of AD and AD-related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN-mediated dephosphorylation of a non-NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild-type mice (3-4 months old) infused with oligomeric Aβ peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild-type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aβ plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging-related disorders.
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http://dx.doi.org/10.1111/acel.13416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282246PMC
July 2021

Multimodal imaging and genetic findings in a case of ARSG-related atypical Usher syndrome.

Ophthalmic Genet 2021 06 25;42(3):338-343. Epub 2021 Feb 25.

Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA.

: Atypical Usher syndrome has recently been associated with arylsulfatase G ( variants. In these cases, characteristic findings include progressive sensorineural hearing loss (SNHL) without vestibular involvement and ring-shaped late-onset retinitis pigmentosa (RP). One patient with atypical Usher syndrome and a novel homozygous variant was included in this study. The patient underwent a comprehensive ophthalmic examination, including multimodal imaging and genetic testing. A 60-year-old male of Persian decent presented to our clinic with a history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Consistent with previous reports of -related atypical Usher syndrome, fundus examination revealed ring-shaped retinal hyperpigmentation and fundus autofluorescence (FAF) demonstrated a six-zone pattern of autofluorescence. Optical coherence tomography (OCT) showed extensive cystoid spaces concentrated in the ganglion cell layer. Widefield OCT angiography at the level of the choriocapillaris showed signs of atrophy that corresponded to the FAF hypofluorescent zone. The patient was homozygous for a novel variant c. 1270 C > T, p. Arg424Cys. We report a novel variant in a case of atypical Usher syndrome and describe multimodal imaging findings that further characterize the effect of in the pathogenesis of atypical Usher syndrome.
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http://dx.doi.org/10.1080/13816810.2021.1891552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154670PMC
June 2021

Tau drives translational selectivity by interacting with ribosomal proteins.

Acta Neuropathol 2019 04 13;137(4):571-583. Epub 2019 Feb 13.

Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, BOX 100159, Gainesville, FL, 32610, USA.

There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and found that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis under translational control of rpS6 was reduced under tauopathic conditions in Alzheimer's disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, since regulation of protein synthesis is critical for learning and memory, aberrant tau-ribosome interactions in disease could explain the linkage between tauopathies and cognitive impairment.
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http://dx.doi.org/10.1007/s00401-019-01970-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426815PMC
April 2019
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