Polyglutamine Repeat Length-Dependent Proteolysis of Huntingtin

Sun, Bee-Chun; Fan, Wei; Balciunas, Aldona M.; Cooper, Joseph; Bitan, Gal; Steavenson, Shirley; Denis, Paul; Young, Yunjen; Adler, Beverly S.; Daugherty, Larry; Manoukian, Raffi; Elliott, Gary; Shen, Wenyan David; Talvenheimo, Jane; Teplow, David B.; Haniu, Mitsuru; Haldankar, Raj; Wypych, Jette; Ross, Christopher A.; Citron, Martin; Richards, William G.

doi:10.1006/nbdi.2002.0539

Cited by 39 publications

(37 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The protease(s) involved remain to be determined. It could be a caspase cleaving at 214-EAND-217 (Berke et al, 2004) or, as reported for the cleavage fragment of other polyglutamine disease proteins, calpain or aspartic endopeptidases acting in concert with the proteasome (Kim et al, 2001;Gafni and Ellerby, 2002;Lunkes et al, 2002;Sun et al, 2002;Gafni et al, 2004). We expect that the mutant ataxin-3 fragment in our transgenic mouse brain will serve as a reference to identify a cell model and cellular components relevant to the appropriate processing of the disease protein.…”

Section: Mutant Ataxin-3 Putative-cleavage Fragmentmentioning

confidence: 85%

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Goti¹,

Katzen²,

Mez³

et al. 2004

J. Neurosci.

180

244

View full text Add to dashboard Cite

Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by ataxin-3 with a polyglutamine expansion. It isproposed that a toxic cleavage fragment of mutant ataxin-3 alternatively spliced isoform mjd1a triggers neurodegeneration, although this fragment has not yet been detected in the brains of MJD patients or in animal models. We have now generated transgenic mice expressing human mutant (Q71) or normal (Q20) ataxin-3 mjd1a under the control of the mouse prion promoter. Q71 transgenic mice expressing mutant ataxin-3 mjd1a above a critical level developed a phenotype similar to MJD including progressive postural instability, gait and limb ataxia, weight loss, premature death, neuronal intranuclear inclusions, and decreased tyrosine hydroxylase-positive neurons in the substantia nigra (determined by unbiased stereology). Q20 transgenic mice had normal behavior and pathology. Brains from sick Q71 transgenic mice contained an abundant mutant ataxin-3 mjd1a putative-cleavage fragment (Fragment), which was scarce in normal Q71 transgenic mice. Reactivity of the Fragment with a panel of antibodies and comigration with truncations of mutant ataxin-3 revealed that it contained residues C terminal to amino acid 221 to include the polyglutamine expansion. A similar portion of mutant ataxin-3 mjd1a expressed in transfected neuroblastoma cells was toxic above a critical concentration. The Fragment was more abundant in two affected brain regions of MJD patients. Thus, we have developed a murine model for mutant ataxin-3 mjd1a toxicity and identified a putativecleavage fragment of the disease protein in the brains of these transgenic mice and MJD patients that is cytotoxic above a critical concentration.

show abstract

Section: Mutant Ataxin-3 Putative-cleavage Fragmentmentioning

confidence: 85%

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Goti¹,

Katzen²,

Mez³

et al. 2004

J. Neurosci.

180

244

View full text Add to dashboard Cite

show abstract

“…The mechanisms of Htt induced toxicity are still largely unknown; however, there is mounting evidence that toxic poly(Q)-expanded Htt fragments are formed from fulllength Htt via proteolysis (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Thus, the Htt cleavage pathway and the molecules involved in it may represent potential therapeutic targets for intervention in HD.…”

Section: Huntington Disease (Hd)mentioning

confidence: 99%

Mutant Huntingtin N-terminal Fragments of Specific Size Mediate Aggregation and Toxicity in Neuronal Cells

Ratovitski

Guček

Jiang

et al. 2009

Journal of Biological Chemistry

Self Cite

124

123

View full text Add to dashboard Cite

Huntingtin proteolysis is implicated in Huntington diseasepathogenesis, yet, the nature of huntingtin toxic fragments remains unclear. Huntingtin undergoes proteolysis by calpains and caspases within an N-terminal region between amino acids 460 and 600. We have focused on proteolytic steps producing shorter N-terminal fragments, which we term cp-1 and cp-2 (distinct from previously described cp-A/cp-B). We used HEK293 cells to express the first 511 residues of huntingtin and further define the cp-1 and cp-2 cleavage sites. Based on epitope mapping with huntingtin-specific antibodies, we found that cp-1 cleavage occurs between residues 81 and 129 of huntingtin. Affinity and size exclusion chromatography were used to further purify huntingtin cleavage products and enrich for the cp-1/ cp-2 fragments. Using mass spectrometry, we found that the cp-2 fragment is generated by cleavage of huntingtin at position Arg 167 . This site was confirmed by deletion analysis and specific detection with a custom-generated cp-2 site neo-epitope antibody. Furthermore, alterations of this cleavage site resulted in a decrease in toxicity and an increase in aggregation of huntingtin in neuronal cells. These data suggest that cleavage of huntingtin at residue Arg 167 may mediate mutant huntingtin toxicity in Huntington disease.

show abstract

“…6), an enzyme linked to a diverse array of pathologies. Calpain, like cathepsin D, is thought to produce aberrant fragments that assemble, or trigger the assembly of, aberrant intracellular structures such as the inclusions that characterize Huntington's Disease (Sun et al, 2002). The huntingtin protein fragments accumulate in the nucleus where they may gain access to the cell's transcription apparatus.…”

Section: Relationship Of Plasticity Deficits To Generalized Brain Agingmentioning

confidence: 99%

Synaptic plasticity in early aging

Lynch

Rex

Gall

2006

Ageing Research Reviews

View full text Add to dashboard Cite

Studies of how aging affects brain plasticity have largely focused on old animals. However, deterioration of memory begins well in advance of old age in animals, including humans; the present review is concerned with the possibility that changes in synaptic plasticity, as found in the long-term potentiation (LTP) effect, are responsible for this. Recent results indicate that impairments to LTP are in fact present by early middle age in rats but only in certain dendritic domains. The search for the origins of these early aging effects necessarily involves ongoing analyses of how LTP is induced, expressed, and stabilized. Such work points to the conclusion that cellular mechanisms responsible for LTP are redundant and modulated both positively and negatively by factors released during induction of potentiation. Tests for causes of the localized failure of LTP during early aging suggest that the problem lies in excessive activity of a negative modulator. The view of LTP as having redundant and modulated substrates also suggests a number of approaches for reversing age-related losses. Particular attention will be given to the idea that induction of brain-derived neurotrophic factor, an extremely potent positive modulator, can be used to provide long periods of normal plasticity with very brief pharmacological interventions. The review concludes with a consideration of how the selective, regional deficits in LTP found in early middle age might be related to the global phenomenon of brain aging. #

show abstract

Polyglutamine Repeat Length-Dependent Proteolysis of Huntingtin

Cited by 39 publications

References 39 publications

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Mutant Huntingtin N-terminal Fragments of Specific Size Mediate Aggregation and Toxicity in Neuronal Cells

Synaptic plasticity in early aging

Contact Info

Product

Resources

About