scholarly journals Loss of Hap1 selectively promotes striatal degeneration in Huntington disease mice

2020 ◽  
Vol 117 (33) ◽  
pp. 20265-20273 ◽  
Author(s):  
Qiong Liu ◽  
Siying Cheng ◽  
Huiming Yang ◽  
Louyin Zhu ◽  
Yongcheng Pan ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Cellular Stress ◽  
Neuronal Loss ◽  
Ideal Model ◽  
Adeno Associated Virus ◽  
Multiple Factors ◽  
Striatal Degeneration ◽  
Mouse Striatum

Huntington disease (HD) is an ideal model for investigating selective neurodegeneration, as expanded polyQ repeats in the ubiquitously expressed huntingtin (HTT) cause the preferential neurodegeneration in the striatum of the HD patient brains. Here we report that adeno-associated virus (AAV) transduction-mediated depletion of Hap1, the first identified huntingtin-associated protein, in adult HD knock-in (KI) mouse brains leads to selective neuronal loss in the striatum. Further, Hap1 depletion-mediated neuronal loss via AAV transduction requires the presence of mutant HTT. Rhes, a GTPase that is enriched in the striatum and sumoylates mutant HTT to mediate neurotoxicity, binds more N-terminal HTT when Hap1 is deficient. Consistently, more soluble and sumoylated N-terminal HTT is presented in HD KI mouse striatum when HAP1 is absent. Our findings suggest that both Rhes and Hap1 as well as cellular stress contribute to the preferential neurodegeneration in HD, highlighting the involvement of multiple factors in selective neurodegeneration.

scholarly journals A Case of Previously Unsuspected Huntington Disease Diagnosed at Autopsy

2017 ◽  
Vol 7 (1) ◽  
pp. 136-144
Author(s):  
Catherine R. Miller ◽  
Nobby C. Mambo ◽  
Jianli Dong ◽  
Gerald A. Campbell
Keyword(s):  
Genetic Testing ◽  
Huntington Disease ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Case Reports ◽  
Neuronal Loss ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Psychiatric Disturbances ◽  
Personality Changes

Huntington disease (HD) is a neurodegenerative disorder with a worldwide prevalence of four to ten per 100 000. It is characterized by choreiform movements, behavioral/psychiatric disturbances, and eventual cognitive decline. Symptoms usually present between 30 and 50 years of age and the diagnosis is based on the combination of clinical symptoms, family history, and genetic testing. A variation of HD, juvenile Huntington disease (JHD), presents earlier, with more severe symptoms and with a worse prognosis. Symptoms are different in JHD, with personality changes and learning difficulties being the predominant presenting features. Seizures are common in JHD, and chorea is uncommon; movement disorders at presentation of JHD are predominantly nonchoreiform. The inheritance pattern for both HD and JHD is autosomal dominant and the disease is caused by an elongation of the CAG repeat in the huntingtin gene. There are many published case reports of Huntington disease that were confirmed at autopsy, but to our knowledge, there are no reports in the literature where the diagnosis of Huntington disease was first made at autopsy. We present a case of a 28-year-old African-American male who was in a state of neglect due to a lifetime of abuse, cognitive difficulties, and seizures, whose cause of death was pneumonia. The gross autopsy findings included bilateral caudate nucleus atrophy and lateral ventricular dilation. Microscopically, severe bilateral neuronal loss and gliosis of the caudate and putamen nuclei were seen. Genetic testing for the number of CAG repeats confirmed the diagnosis and was consistent with JHD.

scholarly journals Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease

2016 ◽  
pp. ddw122 ◽  
Author(s):  
Roy Tang Yi Teo ◽  
Xin Hong ◽  
Libo Yu-Taeger ◽  
Yihui Huang ◽  
Liang Juin Tan ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Neuronal Loss

scholarly journals The Interaction of Aging and Cellular Stress Contributes to Pathogenesis in Mouse and Human Huntington Disease Neurons

2020 ◽  
Vol 12 ◽  
Author(s):  
Emily Machiela ◽  
Ritika Jeloka ◽  
Nicholas S. Caron ◽  
Shagun Mehta ◽  
Mandi E. Schmidt ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Cellular Stress

scholarly journals Metabolic State Determines Sensitivity to Cellular Stress in Huntington Disease: Normalization by Activation of PPARγ

PLoS ONE ◽  
2012 ◽  
Vol 7 (1) ◽  
pp. e30406 ◽  
Author(s):  
Youngnam N. Jin ◽  
Woong Y. Hwang ◽  
Chulman Jo ◽  
Gail V. W. Johnson
Keyword(s):  
Huntington Disease ◽  
Cellular Stress ◽  
Metabolic State

scholarly journals Adeno-associated virus-mediated expression of β-hexosaminidase prevents neuronal loss in the Sandhoff mouse brain

2011 ◽  
Vol 20 (22) ◽  
pp. 4371-4380 ◽  
Author(s):  
Timothy J. Sargeant ◽  
Susan Wang ◽  
Josephine Bradley ◽  
Nicolas J.C. Smith ◽  
Animesh A. Raha ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Neuronal Loss ◽  
Adeno Associated Virus

scholarly journals Nucleolar stress controls mutant Huntingtin toxicity and monitors Huntington disease progression

2021 ◽  
Author(s):  
Aynur Soenmez ◽  
Rasem Mustafa ◽  
Salome T Ryll ◽  
Francesca Tuorto ◽  
Ludivine Wacheul ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mouse Model ◽  
Huntington Disease ◽  
Neurodegenerative Disorder ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Cag Repeats ◽  
Mutant Huntingtin ◽  
The Impact

Transcriptional and cellular stress surveillance deficits are hallmarks of Huntington disease (HD), a fatal autosomal dominant neurodegenerative disorder, caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD remain unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo is elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases mHTT disperse state in the nucleus, exacerbating the motor deficits. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its nucleolar localization. NPM1 de-localization occurs in the striatum and in the skeletal muscle of the progressive zQ175 knock-in HD mouse model, mimicking the phenotype of HD patients in skeletal muscle biopsies. Taken together, we showed that nucleolar integrity regulates the formation of mHTT inclusions in vivo, and identified NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.

Huntington Disease

2017 ◽  
Author(s):  
Roger L. Albin ◽  
Henry L. Paulson
Keyword(s):  
Genetic Testing ◽  
Supportive Care ◽  
Effective Treatment ◽  
Huntington Disease ◽  
Neurodegenerative Disorders ◽  
Brain Regions ◽  
Repeat Family ◽  
Cognitive Changes ◽  
Striatal Degeneration ◽  
Widespread Availability

A member of the expanded polyglutamine (polyQ) repeat family of neurodegenerative disorders, Huntington disease (HD) is a rare, autosomal, dominantly inherited neuropsychiatric disorder. Characterized by midlife onset, HD exhibits progressive motor, behavioral, and cognitive changes. There is no effective treatment and death usually ensues 15 to 20 years after diagnosis. The expanded polyglutamine repeat causes multiple cellular dysfunctions to induce neurodegeneration. Many brain regions are affected in HD though striatal degeneration is particularly prominent. Widespread availability of specific genetic testing facilitates diagnosis. Management is largely supportive care.

scholarly journals Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease

2019 ◽  
Vol 116 (19) ◽  
pp. 9622-9627 ◽  
Author(s):  
Costanza Ferrari Bardile ◽  
Marta Garcia-Miralles ◽  
Nicholas S. Caron ◽  
Nirmala Arul Rayan ◽  
Sarah R. Langley ◽  
...  
Keyword(s):  
White Matter ◽  
Huntington Disease ◽  
Behavioral Outcomes ◽  
Neuronal Loss ◽  
Secondary Outcome ◽  
Pathological Feature ◽  
Behavioral Deficits ◽  
Polycomb Repressive Complex 2 ◽  
Behavioral Abnormalities ◽  
White Matter Pathology

White matter abnormalities are a nearly universal pathological feature of neurodegenerative disorders including Huntington disease (HD). A long-held assumption is that this white matter pathology is simply a secondary outcome of the progressive neuronal loss that manifests with advancing disease. Using a mouse model of HD, here we show that white matter and myelination abnormalities are an early disease feature appearing before the manifestation of any behavioral abnormalities or neuronal loss. We further show that selective inactivation of mutant huntingtin (mHTT) in the NG2+ oligodendrocyte progenitor cell population prevented myelin abnormalities and certain behavioral deficits in HD mice. Strikingly, the improvements in behavioral outcomes were seen despite the continued expression of mHTT in nonoligodendroglial cells including neurons, astrocytes, and microglia. Using RNA-seq and ChIP-seq analyses, we implicate a pathogenic mechanism that involves enhancement of polycomb repressive complex 2 (PRC2) activity by mHTT in the intrinsic oligodendroglial dysfunction and myelination deficits observed in HD. Our findings challenge the long-held dogma regarding the etiology of white matter pathology in HD and highlight the contribution of epigenetic mechanisms to the observed intrinsic oligodendroglial dysfunction. Our results further suggest that ameliorating white matter pathology and oligodendroglial dysfunction may be beneficial for HD.

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