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Loss of huntingtin function slows synaptic vesicle endocytosis in striatal neurons from the httQ140/Q140 mouse model of Huntington's disease.
Abstract Huntington's disease (HD) is caused by CAG repeat expansion within the HTT gene, with the dysfunction and eventual loss of striatal medium spiny neurons a notable feature. Since medium spiny neurons receive high amounts of synaptic input, we hypothesised that this vulnerability originates from an inability to sustain presynaptic performance during intense neuronal activity. To test this hypothesis, primary cultures of either hippocampal or striatal neurons were prepared from either wild-type mice or a knock-in HD mouse model which contains 140 poly-glutamine repeats in the huntingtin protein (httQ140/Q140...
Source: Neurobiology of Disease - October 11, 2019 Category: Neurology Authors: McAdam RL, Morton A, Gordon SL, Alterman JF, Khvorova A, Cousin MA, Smillie KJ Tags: Neurobiol Dis Source Type: research

RNAi mechanisms in Huntington ’s disease therapy: siRNA versus shRNA
AbstractHuntington ’s Disease (HD) is a genetically dominant trinucleotide repeat disorder resulting from CAG repeats within the Huntingtin (HTT) gene exceeding a normal range (>  36 CAGs). Symptoms of the disease manifest in middle age and include chorea, dystonia, and cognitive decline. Typical latency from diagnosis to death is 20 years. There are currently no disease-modifying therapies available to HD patients. RNAi is a potentially curative therapy for HD. A popular line of research employs siRNA or antisense oligonucleotides (ASO) to knock down mutant Huntingtin mRNA (mHTT). Unfortunately, this modality requ...
Source: Translational Neurodegeneration - November 27, 2017 Category: Neurology Source Type: research

Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington's disease.
Abstract The sigma-1 receptor (SIGMAR1) is one of the endoplasmic reticulum (ER) chaperones, which participate in the degradation of misfolded proteins via the ER-related degradation machinery linked to the ubiquitin-proteasome pathway. ER dysfunction in the formation of inclusion bodies in various neurodegenerative diseases has also become evident. Recently, we demonstrated that accumulation of SIGMAR1 was common to neuronal nuclear inclusions in polyglutamine diseases including Huntington's disease. Our study also indicated that SIGMAR1 might shuttle between the cytoplasm and the nucleus. In the present study, w...
Source: Neurobiology of Disease - November 14, 2014 Category: Neurology Authors: Miki Y, Tanji K, Mori F, Wakabayashi K Tags: Neurobiol Dis Source Type: research

Polyglutamine Disease Modeling: Epitope Based Screen for Homologous Recombination using CRISPR/Cas9 System
Discussion We show that CRISPR/Cas9 system can be utilized to perform homologous recombination in human cells to generate a HD isogenic allelic series (21, 72, 97 CAG). In our study, we compared the Cas9 vs. Cas9 D10A enzymes for their ability to mediate this event using two distinct endpoints. The use of Cas9 D10A is likely to be more selective with less off target effects. When we compared CRISPR-assisted HR using methylene blue stained clonal colonies it appeared that the wildtype Cas9 was much more effective at mediating HR. However, when we analyzed the same experiment in our 1C2 western blot assay which only detects ...
Source: PLOS Currents Huntington Disease - April 15, 2014 Category: Neurology Authors: mahrucan Source Type: research

Coenzyme Q10, Statin, and Spinocerebellar Ataxias (I11-1.008)
CONCLUSIONS:CoQ10 is associated with better clinical outcome in SCA1, 2, and 3 whereas statins are associated with worse clinical outcome in SCA6. These drug exposures did not appear to influence clinical progression within 2 years. CoQ10 and statins may have only symptomatic effects or require a longer period of time for disease modification.Study Supported by:American Brain Foundation Research Fellowship, Rare Disease Clinical Research Network RC1NS068897, and NINDS K08 NS083738.Disclosure: Dr. Kuo has nothing to disclose. Dr. Lo has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Pulst has received person...
Source: Neurology - April 9, 2014 Category: Neurology Authors: Kuo, S.-H., Lo, R., Figueroa, K., Pulst, S., Perlman, S., Wilmot, G., Gomez, C., Schmahmann, J., Paulson, H., Shakkottai, V., Ying, S., Zesiewicz, T., Bushara, K., Geschwind, M., Xia, G., Subramony, S., Ashizawa, T. Tags: Proteinopathy in Neurodegenerative Disease Poster Presentations Source Type: research

Coenzyme Q10, Statin, and Spinocerebellar Ataxias (P6.047)
CONCLUSIONS:CoQ10 is associated with better clinical outcome in SCA1, 2, and 3 whereas statins are associated with worse clinical outcome in SCA6. These drug exposures did not appear to influence clinical progression within 2 years. CoQ10 and statins may have only symptomatic effects or require a longer period of time for disease modification.Study Supported by:American Brain Foundation Research Fellowship, Rare Disease Clinical Research Network RC1NS068897, and NINDS K08 NS083738.Disclosure: Dr. Kuo has nothing to disclose. Dr. Lo has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Pulst has received person...
Source: Neurology - April 9, 2014 Category: Neurology Authors: Kuo, S.-H., Lo, R., Figueroa, K., Pulst, S., Perlman, S., Wilmot, G., Gomez, C., Schmahmann, J., Paulson, H., Shakkottai, V., Ying, S., Zesiewicz, T., Bushara, K., Geschwind, M., Xia, G., Subramony, S., Ashizawa, T. Tags: Movement Disorders: Spinocerebellar Ataxias Source Type: research