Huntington's disease: CAG genetics expands neurobiology

Gusella, James F.; MacDonald, Marcy E.

doi:10.1016/0959-4388(95)80072-7

Cited by 58 publications

(19 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a matter of fact, the HD gene was the first autosomal disease locus to be mapped by genetic linkage analysis (to chromosome 4q16), in 1983 (86). It took 10 more years to identify the underlying gene defect, which proved to be a poly-CAG (encoding glutamine [Q]) repeat in exonmean repeat length in HD patients is 40-45, although variability is quite wide, ranging from 35 to 120 repeats (88), displaying an inverse correlation with onset age. Interestingly, approximately 10% of all HD cases are considered "de novo," i.e., these cases originate from asymptomatic parents with normal repeat lengths that have expanded to symptomatic range (see below).…”

Section: Huntington Diseasementioning

confidence: 99%

The genetic epidemiology of neurodegenerative disease

Bertram

Tanzi²

2005

Journal of Clinical Investigation

561

345

View full text Add to dashboard Cite

Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes.

show abstract

Section: Huntington Diseasementioning

confidence: 99%

The genetic epidemiology of neurodegenerative disease

Bertram

Tanzi²

2005

Journal of Clinical Investigation

561

345

View full text Add to dashboard Cite

show abstract

“…The neuropathology of HD is a marked neuronal death in the striatum, whereas other brain structures are selectively spared. HD is caused by an abnormally expanded CAG tract in the coding region of the IT15 gene, which encodes a polyglutamine tract in the protein huntingtin (htt) (Gusella and MacDonald, 1995). There is currently no effective treatment to prevent or delay disease progression.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421

et al. 2006

View full text Add to dashboard Cite

“…Huntington disease (HD) 3 is an autosomal dominant disorder caused by an expansion of glutamine residues in the gene encoding the protein huntingtin (Htt) (1). Htt and mutant Htt (mHtt) are ubiquitously expressed throughout the brain and peripheral tissues, yet HD is associated with highly selective degradation of the striatum with no notable alterations in peripheral tissues.…”

mentioning

confidence: 99%

Rhes, a Physiologic Regulator of Sumoylation, Enhances Cross-sumoylation between the Basic Sumoylation Enzymes E1 and Ubc9

Subramaniam

Mealer

Sixt

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

We recently reported that the small G-protein Rhes has the properties of a SUMO-E3 ligase and mediates mutant huntingtin (mHtt) cytotoxicity. We now demonstrate that Rhes is a physiologic regulator of sumoylation, which is markedly reduced in the corpus striatum of Rhes-deleted mice. Sumoylation involves activation and transfer of small ubiquitin-like modifier (SUMO) from the thioester of E1 to the thioester of Ubc9 (E2) and final transfer to lysines on target proteins, which is enhanced by E3s. We show that E1 transfers SUMO from its thioester directly to lysine residues on Ubc9, forming isopeptide linkages. Conversely, sumoylation on E1 requires transfer of SUMO from the thioester of Ubc9. Thus, the process regarded as "autosumoylation" reflects intermolecular transfer between E1 and Ubc9, which we designate "cross-sumoylation." Rhes binds directly to both E1 and Ubc9, enhancing cross-sumoylation as well as thioester transfer from E1 to Ubc9. Huntington disease (HD)3 is an autosomal dominant disorder caused by an expansion of glutamine residues in the gene encoding the protein huntingtin (Htt) (1). Htt and mutant Htt (mHtt) are ubiquitously expressed throughout the brain and peripheral tissues, yet HD is associated with highly selective degradation of the striatum with no notable alterations in peripheral tissues. Rhes, a member of the Ras family of small G-proteins, was identified on the basis of its selective localization to the corpus striatum of the brain, hence its designation as Ras homolog enriched in striatum (2). We recently reported that Rhes binds mHtt selectively and with high avidity to enhance mHtt sumoylation, with Rhes acting as an apparent E3 ligase for mHtt as well as other substrates such as RanGAP and SP100 (3). Sumoylation of mHtt leads to its disaggregation and augmented neurotoxicity (3, 4). Thus, selective striatal neuronal loss in HD may reflect the tissue-specific influence of Rhes on mHtt sumoylation and cytotoxicity.Sumoylation involves a multistep enzymatic cascade analogous to ubiquitination, beginning with the activation and attachment of SUMO as a thioester bond to E1, the Aos1/Uba2 heterodimer. The SUMO group is then transferred from E1 to Ubc9, the E2-conjugating enzyme, as a thioester bond. In the final step, SUMO is transferred to lysine residues of target proteins forming an isopeptide bond, a process enhanced by E3 ligases (5).Sumoylation can regulate protein function through changes in localization, stability, and activity. Because the sumoylation cascade employs only a single E1 (Aos1/Uba2) and a single E2 (Ubc9), regulation of these enzymes could have substantial effects upon sumoylation. SUMO E1 and Ubc9 are themselves sumoylated in yeast and mammalian cells (6, 7). Recently, it was reported that attachment of SUMO at lysine 14 on Ubc9 acts as a molecular switch to modulate sumoylation of target proteins (8). Molecular mechanisms underlying "autosumoylation" of SUMO-E1 and Ubc9 have not hitherto been elucidated.We now report that mice with deletion of Rhes manifest a p...

show abstract

Huntington's disease: CAG genetics expands neurobiology

Cited by 58 publications

References 51 publications

The genetic epidemiology of neurodegenerative disease

The genetic epidemiology of neurodegenerative disease

Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421

Rhes, a Physiologic Regulator of Sumoylation, Enhances Cross-sumoylation between the Basic Sumoylation Enzymes E1 and Ubc9

Contact Info

Product

Resources

About