Therapeutic interventions for symptomatic treatment in Huntington's disease

Author(s):  
Tiago Mestre ◽  
Miguel M Coelho ◽  
João Costa ◽  
Joaquim Ferreira ◽  
Mário Miguel Rosa ◽  
...  
2019 ◽  
Vol 116 (22) ◽  
pp. 10952-10961 ◽  
Author(s):  
Joseph Ochaba ◽  
Gianna Fote ◽  
Marketta Kachemov ◽  
Soe Thein ◽  
Sylvia Y. Yeung ◽  
...  

Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington’s disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.


2012 ◽  
Vol 25 (2) ◽  
pp. 339-340 ◽  
Author(s):  
Suzanne J. Booij ◽  
Dick P. Engberts ◽  
Aad Tibben ◽  
Raymund A. C. Roos

Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disease characterized by chorea, hypokinesia, psychiatric symptoms, and dementia. The age of onset is usually between 30 and 50 years; the duration of illness is from 10–20 years. The rate of suicide in patients is higher than in the general population and is the second most common cause of death in HD after pneumonia (Bindler et al., 2009). Currently, symptomatic treatment is available, but there is no cure. The identification of HD-gene in 1993 made DNA testing possible in individuals at risk.


BJPsych Open ◽  
2021 ◽  
Vol 7 (5) ◽  
Author(s):  
Erik van Duijn ◽  
A. Raquel Fernandes ◽  
Daisy Abreu ◽  
Jennifer J. Ware ◽  
Eileen Neacy ◽  
...  

Background Risk of death from suicide in Huntington's disease is notably elevated relative to that in the general population, although the incidence within HD populations has not been precisely defined. Robust incidence estimates of suicidal behavior can serve as references for HD therapeutic research and post-marketing surveillance to help evaluate the suicidality risk of novel therapeutics. Aims To estimate the incidence rate of completed suicide and suicide attempt in the global, prospective HD cohort study Enroll-HD that records these events per protocol. Method A total of 20 912 participants were available for analysis (HD gene-expansion carriers (HDGECs) n = 15 924; non-HDGECs n = 4988) representing a collective observation period of 53 390 participant-years. Each observed event was subject to clinical review and evaluation. We generated incidence rates (events per 100 000 person-years) for suicides and suicide attempts using all available data, as well as by year of study and geographical region. Proportionate mortality statistics for suicide and respective 95% confidence intervals were also generated. Results The overall incidence rate of suicide in HDGECs was 72 per 100 000 person-years, and 8 per 100 000 person-years in non-HDGECs. Proportionate mortality attributable to suicide in HDGECs was 4.6%. For suicide attempts, the global overall incidence rate observed in HDGECs was 306–375 per 100 000 person-years, and 23–38 per 100 000 person-years in non-HDGECs. Conclusions The incidence estimates calculated here can be used as a reference to help evaluate drug safety and may also be useful in assessing progress in clinical care for HDGECs once therapeutic interventions become widely available.


2021 ◽  
Author(s):  
Daniele Bertoglio ◽  
Jonathan Bard ◽  
Manuela Hessmann ◽  
Longbin Liu ◽  
Annette Gaertner ◽  
...  

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (PolyQ) tract. While several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, no method is currently available to visualize mHTT levels in the living brain. Here we demonstrate the development of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11C ([11C]CHDI-180R) enables non-invasive monitoring of mHTT pathology in the brain and can track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression. We further show that therapeutic agents that lower mHTT in the striatum have a functional restorative effect that can be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.


2012 ◽  
Vol 40 (4) ◽  
pp. 739-745 ◽  
Author(s):  
Edward W. Green ◽  
Flaviano Giorgini

HD (Huntington's disease) is a fatal inherited gain-of-function disorder caused by a polyQ (polyglutamine) expansion in the htt (huntingtin protein). Expression of mutant htt in model organisms is sufficient to recapitulate many of the cellular defects found in HD patients. Many groups have independently developed Drosophila models of HD, taking advantage of its rapid life cycle, carefully annotated genome and well-established molecular toolkits. Furthermore, unlike simpler models, Drosophila have a complex nervous system, displaying a range of carefully co-ordinated behaviours which offer an exquisitely sensitive readout of neuronal disruption. Measuring HD-associated changes in behaviour in Drosophila therefore offers a window into the earliest stages of HD, when therapeutic interventions might be particularly effective. The present review describes a number of recently developed Drosophila models of HD and offers practical guidance on the advantages and disadvantages of various experimental approaches that can be used to screen these models for modifiers of mutant htt-mediated toxicity.


2009 ◽  
Vol 24 (15) ◽  
pp. 2254-2259 ◽  
Author(s):  
Adrienne Curtis ◽  
Ian Mitchell ◽  
Smitaa Patel ◽  
Natalie Ives ◽  
Hugh Rickards

2007 ◽  
Author(s):  
Tiago Mestre ◽  
Miguel M Coelho ◽  
João Costa ◽  
Joaquim Ferreira ◽  
Mário Miguel Rosa ◽  
...  

2020 ◽  
Vol 11 (3) ◽  
pp. 3761-3767
Author(s):  
Hima Bindu Mylapalli ◽  
Ramam Sripada ◽  
Sireesha Maram ◽  
Sudeepthi Padala ◽  
Aksha Susmitha Jangam ◽  
...  

Huntington’s disease (HD) is a rare autosomal dominant, fatal neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioural disruption, psychiatric disturbances and dementia. This condition is characterized by progressive degeneration of neurons within the basal ganglia, primarily the caudate and the putamen. As the disease progresses, neuronal losses occur in the white matter, cerebral cortex and thalamus. In this article, the authors reviewed the genetic aspects, etiological factors, stages of the disease condition along with the signs and symptoms, various diagnostic procedures besides with the pharmacological and non-pharmacological management of the Huntington’s disease. This disease is inherited within the families, and the pathophysiology of Huntington disease is restricted to the brain, where degeneration begins initially in the striatum, spreads to the cortex and eventually appears throughout the brain.The pathogenesis of this disease is still unrevealed, and there is no treatment available for the cure of the disease. There were many drugs of choices available for symptomatic treatment aiming to improve the quality of life in the patient. The non-pharmacological therapy for managing Huntington’s disease includes physiotherapy, speech therapy and psychotherapy.At a therapeutic setting, all the needs of the patients are to be addressed as the advancement in the development of new therapeutic agents are paving the way for the better outcomes in the management of Huntington’s disease and thereby promising better healthcare for these patients.


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