The identification of a functional nuclear localization signal in the Huntington disease protein

Bessert, Denise; Gutridge, Kristin; Dunbar, Joan C.; Carlock, Leon

doi:10.1016/0169-328x(95)00124-b

Cited by 34 publications

(23 citation statements)

References 24 publications

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“…DNA was stained with 4Ј,6-diamidino-2-phenylindole. Similar results were observed on labeling with mAb Hnt, mAb 2166, and rAb HAP40 [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] or HAP40 226 -243 and in transfected HeLa cells.…”

Section: Figsupporting

confidence: 64%

“…Alternatively, several lines of evidence are consistent with regulated active nuclear transport of huntingtin. Huntingtin contains several consensus NLSs (41) and Ͼ10 sequences matching leucine-rich nuclear export signals. 3 Huntingtin is comprised of 10 HEAT repeats (42) plus an additional flanking sequence highly similar to ␤-importin, a key component of the nuclear transport machinery.…”

Section: Figmentioning

confidence: 99%

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Isolation of a 40-kDa Huntingtin-associated Protein

Peters¹,

Ross²

2001

Journal of Biological Chemistry

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Huntington's disease is caused by an expanded CAG trinucleotide repeat coding for a polyglutamine stretch within the huntingtin protein. Currently, the function of normal huntingtin and the mechanism by which expanded huntingtin causes selective neurotoxicity remain unknown. Clues may come from the identification of huntingtin-associated proteins (HAPs). Here, we show that huntingtin copurifies with a single novel 40-kDa protein termed HAP40. HAP40 is encoded by the open reading frame factor VIII-associated gene A (F8A) located within intron 22 of the factor VIII gene. In transfected cell extracts, HAP40 coimmunoprecipitates with full-length huntingtin but not with an N-terminal huntingtin fragment. Recombinant HAP40 is cytoplasmic in the presence of huntingtin but is actively targeted to the nucleus in the absence of huntingtin. These data indicate that HAP40 is likely to contribute to the function of normal huntingtin and is a candidate for involvement in the aberrant nuclear localization of mutant huntingtin found in degenerating neurons in Huntington's disease.

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Section: Figsupporting

confidence: 64%

Section: Figmentioning

confidence: 99%

Isolation of a 40-kDa Huntingtin-associated Protein

Peters¹,

Ross²

2001

Journal of Biological Chemistry

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“…Huntingtin also is associated with microtubules, and, to a lesser extent, with synaptic vesicles (28). The protein also has a nuclear targeting motif (29). GAPDH is predominantly in the cytosol associated with the cytoskeleton and membranes (1).…”

Section: Discussionmentioning

confidence: 99%

Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and α-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length

Cooper

Sheu

Burke

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Several adult-onset neurodegenerative diseases are caused by genes with expanded CAG triplet repeats within their coding regions and extended polyglutamine (Q n ) domains within the expressed proteins. Generally, in clinically affected individuals n > 40. Glyceraldehyde 3-phosphate dehydrogenase binds tightly to four Q n disease proteins, but the significance of this interaction is unknown. We now report that purified glyceraldehyde 3-phosphate dehydrogenase is inactivated by tissue transglutaminase in the presence of glutathione S-transferase constructs containing a Q n domain of pathological length (n ‫؍‬ 62 or 81). The dehydrogenase is less strongly inhibited by tissue transglutaminase in the presence of constructs containing shorter Q n domains (n ‫؍‬ 0 or 10). Purified ␣-ketoglutarate dehydrogenase complex also is inactivated by tissue transglutaminase plus glutathione S-transferase constructs containing pathological-length Q n domains (n ‫؍‬ 62 or 81). The results suggest that tissue transglutaminase-catalyzed covalent linkages involving the larger poly-Q domains may disrupt cerebral energy metabolism in CAG͞Q n expansion diseases.

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“…[26][27][28][29] Fraksiyonasyon çalışmalarında htt'nin bazı kesecik zar proteinleri ile birlikte bulunduğu ve mutant ifadesinin normal nöronal kesecikli taşı-mayı etkilediği ortaya koyulmuştur. 26,30 Diğer bazı araştırmalar ise htt'nin transferin reseptörü ile ilgili olduğunu ve onun düzenlenmesinde demir-cevabı proteini olabileceğini ileri sürmektedir.…”

Section: Htt Protei̇ni̇ni̇n İşlevleri̇unclassified

“…Ayrıca, yabanıl-tip htt sitoplazmaya yerleşirken, artmış poliQ'lu ve endojenik poliP'li mutant htt sitoplazmik kesime uğra-dıktan sonra proteinin N-terminali çekirdeğe yerleşebilir. 28 Mutant htt nükleer reseptör ko-represör (NCoR), SpI ve CREB-bağlanma proteinleri (CBP) ile etkileşim içerisindedir. Böylece, mutant htt ile gen ifadesinin değişimi nörodejenerasyona sebep olabilecek muhtemel mekanizmalardan biri olarak görülebilir.…”

Section: Gen İfadesi̇ Deği̇şi̇mleri̇unclassified

Mechanisms of Toxicity in Huntington’s Disease and the Role of Polyamines in NMDAR-Mediated Excitotoxicity: Review

Tüfekçi¹,

Tunalı²

2012

Turkiye Klinikleri J Med Sci

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201Huntington Hastalığında Toksisite Mekanizmaları ve NMDAR-Aracılı Eksitotoksisitede Poliaminlerin Rolü Ö ÖZ ZE ET T Huntington hastalığı, istemsiz koreik hareketler, bilişsel kayıplar ve psikolojik bozukluklarla karakterize edilen, otozomal dominant geçişli, geç başlangıçlı ve ölümcül bir hastalıktır. Hastalığa sebep olan mutasyon, IT-15 geninin birinci eksonunda tekrar eden CAG bazlarının sayılarındaki artıştır. Mutant genin ifadesi, striyatal gamma aminobütirik asit ileten (GABA-erjik) orta boy dikensi nöronların seçimli ölümüne neden olur. Mutant huntingtin (htt) proteininin konformasyonu, protein yıkımı ve übikütin-proteozom sistemi (UPS), gen yazılımı düzenlemelerin-deki değişimler ve eksitotoksisite, nörodejenerasyonun moleküler mekanizmaları arasındadır. Uyarıcı kimyasalların aşırı miktarı hücreleri sürekli uyararak hassas hücrelerin eksitotoksik ölüm-lerine sebep olurlar. Glutamat da bazal gangliyadan salınan uyarıcı nörotransmiterlerden biridir. Huntington hastalığında striyatal nöronların kaybedilmesi glutamat reseptörü aracılı eksitotoksisitenin patogenezde etkili olabileceğine işaret eder. İyonotrofik glutamat reseptörleri (iGluR) arasın-dan biri olan N-metil-D-Aspartat reseptörleri (NMDAR)'nin uyarılması ve bunu takiben nükleer faktör kappa B (NF ± B) yazılım faktörünün aktivasyonu nöronal ölüm ile sonuçlanır. NMDAR, glutamat bağlanma bölgelerine ek olarak poliamin bağlanma bölgeleri de içerir. Poliaminlerin mutant htt proteininin, NMDAR ve NF ± B yazılım faktörü ile ayrı ayrı ilişki içerisinde olması, bu proteinin, Huntington hastalığında meydana gelen nörodejenerasyonda merkezi bir rol oynayabileceğini düşündürmektedir. Bu nedenle, Huntington hastalığında poliamin metabolizmasının detaylı araştı-rılması ve anlaşılması hastalığın tedavisinde yeni yaklaşımlar üretilmesini sağlayacaktır.A An na ah ht ta ar r K Ke el li im me el le er r: : Huntington hastalığı; NR2A NMDA reseptörü; reseptörler, glutamat; poliaminler A AB BS ST TR RA AC CT T Huntington's Disease is an autosomal dominant, late onset and fatal disorder characterized by involuntary choreic movements, cognitive dysfunction and psychological disturbances. The causative mutation is the expansion of the CAG repeats in the first exon of the IT-15 gene. Mutant gene expression causes selective death of striatal gamma aminobutyric acid releasing (GABA-ergic) medium size spiny neurons. Changes in the conformation of the mutant huntingtin (htt) protein, proteolysis and ubiquitin-proteasome system (UPS), transcriptional disregulation and excitotoxicity are among the molecular mechanisms of neurodegeneration. Excess amounts of excitatory chemicals continuously stimulate the cells and cause excitotoxic death of vulnerable cells. Glutamate is one of the excitatory neurotransmitters released from basal ganglia. The striatal neuron loss in Huntington's Disease points out that glutamate receptor mediated excitotoxicity may play a role in the pathogenesis. Excitation of N-methyl-D-Aspartate receptors (NMDARs), which belong to ionotrophic glutamate recept...

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The identification of a functional nuclear localization signal in the Huntington disease protein

Cited by 34 publications

References 24 publications

Isolation of a 40-kDa Huntingtin-associated Protein

Isolation of a 40-kDa Huntingtin-associated Protein

Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and α-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length

Mechanisms of Toxicity in Huntington’s Disease and the Role of Polyamines in NMDAR-Mediated Excitotoxicity: Review

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