Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple sclerosis (MS) is characterized by inflammatory demyelination of axons and neurodegeneration, the latter inadequately modeled in experimental autoimmune encephalomyelitis (EAE). Susceptibility of inbred mouse strains to EAE is in part determined by major histocompatibility complex haplotype; however, other molecular mechanisms remain elusive. Galectins bind GlcNAc-branched N-glycans attached to surface glycoproteins, forming a molecular lattice that restricts lateral movement and endocytosis of glycoproteins. GlcNAc branching negatively regulates T cell activity and autoimmunity, and when absent in neurons, induces apoptosis in vivo in young adult mice. We find that EAE susceptible mouse strains PL/J, SJL, and NOD have reduced GlcNAc branching. PL/J mice display the lowest levels, partial deficiencies in N-acetylglucosaminyltransferase I, II, and V (i.e. Mgat1, -2, and -5), T cell hyperactivity and spontaneous late onset inflammatory demyelination and neurodegeneration; phenotypes markedly enhanced by Mgat5(+/-) and Mgat5(-/-) backgrounds in a gene dose-dependent manner. Spontaneous disease is transferable and characterized by progressive paralysis, tremor, dystonia, neuronophagia, and axonal damage in both demyelinated lesions and normal white matter, phenocopying progressive MS. Our data identify hypomorphic Golgi processing as an inherited trait that determines susceptibility to EAE, provides a unique spontaneous model of MS, and suggests GlcNAc-branching deficiency may promote T cell-mediated demyelination and neurodegeneration in MS.
 ...
PMID:N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration. 1785 38

THAP1 is a sequence-specific DNA binding factor that regulates cell proliferation through modulation of target genes such as the cell cycle-specific gene RRM1. Mutations in the THAP1 DNA binding domain, an atypical zinc finger (THAP-zf), have recently been found to cause DYT6 dystonia, a neurological disease characterized by twisting movements and abnormal postures. In this study, we report that THAP1 shares sequence characteristics, in vivo expression patterns and protein partners with THAP3, another THAP-zf protein. Proteomic analyses identified HCF-1, a potent transcriptional coactivator and cell cycle regulator, and O-GlcNAc transferase (OGT), the enzyme that catalyzes the addition of O-GlcNAc, as major cellular partners of THAP3. THAP3 interacts with HCF-1 through a consensus HCF-1-binding motif (HBM), a motif that is also present in THAP1. Accordingly, THAP1 was found to bind HCF-1 in vitro and to associate with HCF-1 and OGT in vivo. THAP1 and THAP3 belong to a large family of HCF-1 binding factors since seven other members of the human THAP-zf protein family were identified, which harbor evolutionary conserved HBMs and bind to HCF-1. Chromatin immunoprecipitation (ChIP) assays and RNA interference experiments showed that endogenous THAP1 mediates the recruitment of HCF-1 to the RRM1 promoter during endothelial cell proliferation and that HCF-1 is essential for transcriptional activation of RRM1. Together, our findings suggest HCF-1 is an important cofactor for THAP1. Interestingly, our results also provide an unexpected link between DYT6 and DYT3 (X-linked dystonia-parkinsonism) dystonias because the gene encoding the THAP1/DYT6 protein partner OGT maps within the DYT3 critical region on Xq13.1.
 ...
PMID:The THAP-zinc finger protein THAP1 associates with coactivator HCF-1 and O-GlcNAc transferase: a link between DYT6 and DYT3 dystonias. 2020 Jan 53