Huntington???s Disease: What We Learned From the Original Essay

Okun, Michael S.

doi:10.1097/01.nrl.0000080952.78533.1f

Cited by 8 publications

(5 citation statements)

References 14 publications

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“…1981), especially early in the disease. These movements were signature features in the original description of the disease as Huntington’s chorea (Okun 2003). In addition to the relentless decline in motor function, non‐motor disturbances such as cognitive impairments, personality changes, depression, and behavioral disturbances are commonly seen in HD patients, and represent the more serious issues for their families, friends and caregivers (Walker 2007).…”

Section: Hd Brain Pathologymentioning

confidence: 98%

Differential vulnerability of neurons in Huntington’s disease: the role of cell type‐specific features

Han

You

Kordower

et al. 2010

Journal of Neurochemistry

142

117

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J. Neurochem. (2010) 113, 1073–1091. Abstract Abnormal expansion of a polyglutamine tract in huntingtin (Htt) protein results in Huntington’s disease (HD), an autosomal dominant neurodegenerative disorder involving progressive loss of motor and cognitive function. Contrasting with the ubiquitous tissue expression of polyglutamine‐expanded Htt, HD pathology is characterized by the increased vulnerability of specific neuronal populations within the striatum and the cerebral cortex. Morphological, biochemical, and functional characteristics of neurons affected in HD that might render these cells more vulnerable to the toxic effects of polyglutamine‐Htt are covered in this review. The differential vulnerability of neurons observed in HD is discussed in the context of various major pathogenic mechanisms proposed to date, and in line with evidence showing a ‘dying‐back’ pattern of degeneration in affected neuronal populations.

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Section: Hd Brain Pathologymentioning

confidence: 98%

Differential vulnerability of neurons in Huntington’s disease: the role of cell type‐specific features

Han

You

Kordower

et al. 2010

Journal of Neurochemistry

142

117

View full text Add to dashboard Cite

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“…Huntington’s disease (HD) is an autosomal dominant, adult-onset neurodegenerative disease 1 . Patients with a single mutant huntingtin (Htt) gene develop symptoms in midlife with 100% penetrance.…”

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confidence: 99%

Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin

et al. 2009

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Selected vulnerability of neurons in Huntington’s disease (HD) suggests alterations in a cellular process particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal HD models (mouse and squid), but the molecular basis of this effect remains unknown. Here we show that polyQ-Htt inhibits FAT through a mechanism involving activation of axonal JNK. Accordingly, increased activation of JNK was observed in vivo in cellular and animal HD models. Additional experiments indicate that polyQ-Htt effects on FAT are mediated by the neuron-specific JNK3, and not ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in HD. Mass spectrometry identified a residue in the kinesin-1 motor domain phosphorylated by JNK3, and this modification reduces kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provides a molecular basis for polyQ-Htt-induced inhibition of FAT.

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“…[1][2][3][4] Hastalık çoğunlukla 30-50 yaşları arasında ortaya çıkar; ancak 20 yaş ve öncesinde görü-len jüvenil formuna vakaların yaklaşık %10'unda rastlanır. 5 Hastalığın görülme sıklığı Avrupa popü-lasyonlarında 1/10,000 olup, dünya üzerindeki tüm etnik gruplarda tanımlanmıştır.…”

Section: Hunti̇ngton Hastaliğinda Kli̇ni̇k Ve Patoloji̇k Bulgularunclassified

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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Huntington???s Disease: What We Learned From the Original Essay

Abstract: Accurate descriptions before and after Huntington's essay about hereditary chorea have provided humanity to sufferers and the nidus for new discovery within the field of movement disorders.

Cited by 8 publications

References 14 publications

Differential vulnerability of neurons in Huntington’s disease: the role of cell type‐specific features

Differential vulnerability of neurons in Huntington’s disease: the role of cell type‐specific features

Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin

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

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