Ali Khoshnan, PhD

We study the molecular pathogenesis of Huntington’s disease (HD), a genetically inherited neurodegenerative disorder caused by expansion of a polyglutamine repeat in huntingtin protein (HTT). Mutant HTT is amyloidogenic and forms neurotoxic assemblies, which disrupt various signaling pathways and promote neurodegeneration. Patients develop debilitating motor, psychiatric, and cognitive symptoms.

Areas of interest

•Use human neurons, brain organoids, mice and Drosophila models to identify pathogenic assemblies of mutant HTT, study the mechanism of how assemblies spread and propagate in the nervous system, and characterize the neuronal pathways, which regulate neurodegeneration in HD.

•Produce and engineer antibodies and nanobodies targeting the pathogenic conformations of mutant HTT for diagnostic and therapeutic applications.

•Investigate the impact of microbiota-gut-brain pathways on the pathogenesis of HD in Drosophila and mouse models. In this project, we are characterizing the role of HTT in regulating microbial homeostasis in the gut, examining how mutant HTT disrupts these communications and triggers aberrant expression of genes implicated in brain development and physiology, and identifying the gut-brain circuits, which contribute to the onset of various HD symptoms.

•Develop gut-based therapies for HD.

• IKKß signaling mediates metabolic changes in the hypothalamus of a Huntington disease mouse model iScience. 2022 Feb 18; 25(2):103771. . View in PubMed
• Gut Bacteria Regulate the Pathogenesis of Huntington’s Disease in Drosophila Model Front Neurosci. 2022; 16:902205. . View in PubMed
• Corrigendum: Gut bacteria regulate the pathogenesis of Huntington’s disease in Drosophila model Front Neurosci. 2022; 16:991513. . View in PubMed
• Amplification of neurotoxic HTTex1 assemblies in human neurons Neurobiol Dis. 2021 11; 159:105517. . View in PubMed
• Small, Seeding-Competent Huntingtin Fibrils Are Prominent Aggregate Species in Brains of zQ175 Huntington’s Disease Knock-in Mice Front Neurosci. 2021; 15:682172. . View in PubMed
• Identification of distinct conformations associated with monomers and fibril assemblies of mutant huntingtin Hum Mol Genet. 2018 07 01; 27(13):2330-2343. . View in PubMed
• IKKß and mutant huntingtin interactions regulate the expression of IL-34: implications for microglial-mediated neurodegeneration in HD Hum Mol Genet. 2017 11 01; 26(21):4267-4277. . View in PubMed
• DJ-1 modulates aggregation and pathogenesis in models of Huntington’s disease Hum Mol Genet. 2014 Feb 01; 23(3):755-66. . View in PubMed
• Antibodies and intrabodies against huntingtin: production and screening of monoclonals and single-chain recombinant forms Methods Mol Biol. 2013; 1010:231-51. . View in PubMed
• Elevated IKKa accelerates the differentiation of human neuronal progenitor cells and induces MeCP2-dependent BDNF expression PLoS One. 2012; 7(7):e41794. . View in PubMed
• Neurobiol Dis. 2011 Aug; 43(2):305-11. . View in PubMed
• IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome J Cell Biol. 2009 Dec 28; 187(7):1083-99. . View in PubMed
• IKKalpha and IKKbeta regulation of DNA damage-induced cleavage of huntingtin PLoS One. 2009 Jun 02; 4(6):e5768. . View in PubMed
• Intrabodies binding the proline-rich domains of mutant huntingtin increase its turnover and reduce neurotoxicity J Neurosci. 2008 Sep 03; 28(36):9013-20. . View in PubMed
• Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity J Neurosci. 2004 Sep 15; 24(37):7999-8008. . View in PubMed
• Antibodies against huntingtin: production and screening of monoclonals and single-chain recombinant forms Methods Mol Biol. 2004; 277:87-102. . View in PubMed
• Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity Proc Natl Acad Sci U S A. 2002 Jan 22; 99(2):1002-7. . View in PubMed
• The physical association of protein kinase C theta with a lipid raft-associated inhibitor of kappa B factor kinase (IKK) complex plays a role in the activation of the NF-kappa B cascade by TCR and CD28 J Immunol. 2000 Dec 15; 165(12):6933-40. . View in PubMed
• Response differences between human CD4(+) and CD8(+) T-cells during CD28 costimulation: implications for immune cell-based therapies and studies related to the expansion of double-positive T-cells during aging Clin Immunol. 2000 Sep; 96(3):187-97. . View in PubMed
• The NF-kappa B cascade is important in Bcl-xL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes J Immunol. 2000 Aug 15; 165(4):1743-54. . View in PubMed
• Primary human CD4+ T cells contain heterogeneous I kappa B kinase complexes: role in activation of the IL-2 promoter J Immunol. 1999 Nov 15; 163(10):5444-52. . View in PubMed
• Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis J Virol. 1998 May; 72(5):3691-7. . View in PubMed
• Involvement of dsRNA virus in the protein composition and growth kinetics of host Trichomonas vaginalis Arch Virol. 1997; 142(5):939-52. . View in PubMed
• Characterization of double-stranded RNA satellites associated with the Trichomonas vaginalis virus J Virol. 1995 Nov; 69(11):6892-7. . View in PubMed
• Unique double-stranded RNAs associated with the Trichomonas vaginalis virus are synthesized by viral RNA-dependent RNA polymerase J Virol. 1994 Nov; 68(11):7108-14. . View in PubMed
• Trichomonas vaginalis with a double-stranded RNA virus has upregulated levels of phenotypically variable immunogen mRNA J Virol. 1994 Jun; 68(6):4035-8. . View in PubMed
• Multiple double-stranded RNA segments are associated with virus particles infecting Trichomonas vaginalis J Virol. 1993 Dec; 67(12):6950-5. . View in PubMed

• Langen, Ralf
• Siemer, Ansgar
• Pandey, Nitin