Neural Transplantation for Huntington's Disease: Experimental Rationale and Recommendations for Clinical Trials

1996 ◽  
Vol 5 (2) ◽  
pp. 339-352 ◽  
Author(s):  
Kathleen M. Shannon ◽  
Jeffrey H. Kordower
Keyword(s):  
Clinical Trials ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Treatment Strategies ◽  
Neural Transplantation ◽  
Trophic Factors ◽  
Trophic Factor ◽  
Striatal Neurons ◽  
Variable Parameters

Huntington's disease (HD) is a neurodegenerative disorder affecting motor function, personality, and cognition. This paper reviews the experimental data that demonstrate the potential for transplantation of fetal striatum and trophic factor secreting cells to serve as innovative treatment strategies for HD. Transplantation strategies have been effective in replacing lost neurons or preventing the degeneration of neurons destined to die in both rodent and nonhuman primate models of HD. In this regard, a logical series of investigations has proven that grafts of fetal striatum survive, reinnervate the host, and restore function impaired following excitotoxic lesions of the striatum. Furthermore, transplants of cells genetically modified to secrete trophic factors such as nerve growth factor protect striatal neurons from degeneration due to excitotoxicity or mitochondrial dysfunction. Given the disabling and progressive nature of HD, coupled with the absence of any meaningful medical therapy, it is reasonable to consider clinical trials of neural transplantation for this disease. Fetal striatal implants will most likely be the first transplant strategy attempted for HD. This paper describes the variable parameters we believe to be critical for consideration for the design of clinical trials using fetal striatal implants for the treatment of HD.

scholarly journals Bioenergetic deficits in Huntington’s disease iPSC-derived neural cells and rescue with glycolytic metabolites

2019 ◽  
Vol 29 (11) ◽  
pp. 1757-1771 ◽  
Author(s):  
◽  
Amanda J Kedaigle ◽  
Ernest Fraenkel ◽  
Ranjit S Atwal ◽  
Min Wu ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Induced Pluripotent Stem Cell ◽  
Therapeutic Benefit ◽  
Neural Cells ◽  
Striatal Neurons ◽  
Proteomics Data ◽  
Postmortem Human Brain ◽  
Atp Levels

Abstract Altered cellular metabolism is believed to be an important contributor to pathogenesis of the neurodegenerative disorder Huntington’s disease (HD). Research has primarily focused on mitochondrial toxicity, which can cause death of the vulnerable striatal neurons, but other aspects of metabolism have also been implicated. Most previous studies have been carried out using postmortem human brain or non-human cells. Here, we studied bioenergetics in an induced pluripotent stem cell-based model of the disease. We found decreased adenosine triphosphate (ATP) levels in HD cells compared to controls across differentiation stages and protocols. Proteomics data and multiomics network analysis revealed normal or increased levels of mitochondrial messages and proteins, but lowered expression of glycolytic enzymes. Metabolic experiments showed decreased spare glycolytic capacity in HD neurons, while maximal and spare respiratory capacities driven by oxidative phosphorylation were largely unchanged. ATP levels in HD neurons could be rescued with addition of pyruvate or late glycolytic metabolites, but not earlier glycolytic metabolites, suggesting a role for glycolytic deficits as part of the metabolic disturbance in HD neurons. Pyruvate or other related metabolic supplements could have therapeutic benefit in HD.

Huntington’s disease

2020 ◽  
pp. 83-92
Author(s):  
Juliana R Dutra ◽  
Tanya P Garcia ◽  
Karen Marder
Keyword(s):  
Clinical Trials ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Genetic Mutation ◽  
Current Standard ◽  
Disease Modifying ◽  
Disease Modifying Agents ◽  
A Current

Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder caused by an unstable expansion in the cytosine adenine guanine (CAG) trinucleotide repeat in the huntingtin gene. The disease onsets gradually over many years and its symptoms include extrapyramidal movement disorder, cognitive impairment, and behavioural changes. Understanding the overall progression of HD is critical to designing clinical trials with possible disease modifying agents. Research in this area has exploded in the past two decades, as different multicentre studies have evaluated both clinical and biological measures in individuals at different stages of the disease (i.e. at-risk for the genetic mutation, pre-manifest, and manifest HD). In this chapter, we provide readers with a current understanding of HD progression. This includes an overview of the current standard for how HD is clinically evaluated, descriptive epidemiology of the disease, genetics of HD, and a review of potential disease modifiers.

scholarly journals The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kim Le Cann ◽  
Alec Foerster ◽  
Corinna Rösseler ◽  
Andelain Erickson ◽  
Petra Hautvast ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Induced Pluripotent Stem Cell ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Large Variability ◽  
Spiny Neurons ◽  
Induced Pluripotent

AbstractHuntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.

scholarly journals Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

2017 ◽  
Vol 114 (52) ◽  
pp. E11293-E11302 ◽  
Author(s):  
Renee R. Handley ◽  
Suzanne J. Reid ◽  
Rudiger Brauning ◽  
Paul Maclean ◽  
Emily R. Mears ◽  
...  
Keyword(s):  
Human Brain ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cag Repeat ◽  
Causative Mutation ◽  
Striatal Neurons ◽  
Psychological Disturbance ◽  
Postmortem Human Brain ◽  
Sheep Model

The neurodegenerative disorder Huntington’s disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.

scholarly journals Mislocalization of Nucleocytoplasmic Transport Proteins in Human Huntington’s Disease PSC-Derived Striatal Neurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Jenny Lange ◽  
Alison Wood-Kaczmar ◽  
Aneesa Ali ◽  
Sahar Farag ◽  
Rhia Ghosh ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Nucleocytoplasmic Transport ◽  
Cag Repeat ◽  
Nuclear Pore ◽  
Neuronal Cultures ◽  
Striatal Neurons ◽  
Lamin B1 ◽  
Gene And Protein Expression

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). Disease progression is characterized by the loss of vulnerable neuronal populations within the striatum. A consistent phenotype across HD models is disruption of nucleocytoplasmic transport and nuclear pore complex (NPC) function. Here we demonstrate that high content imaging is a suitable method for detecting mislocalization of lamin-B1, RAN and RANGAP1 in striatal neuronal cultures thus allowing a robust, unbiased, highly powered approach to assay nuclear pore deficits. Furthermore, nuclear pore deficits extended to the selectively vulnerable DARPP32 + subpopulation neurons, but not to astrocytes. Striatal neuron cultures are further affected by changes in gene and protein expression of RAN, RANGAP1 and lamin-B1. Lowering total HTT using HTT-targeted anti-sense oligonucleotides partially restored gene expression, as well as subtly reducing mislocalization of proteins involved in nucleocytoplasmic transport. This suggests that mislocalization of RAN, RANGAP1 and lamin-B1 cannot be normalized by simply reducing expression of CAG-expanded HTT in the absence of healthy HTT protein.

scholarly journals Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington’s disease

2011 ◽  
Vol 194 (2) ◽  
pp. 209-227 ◽  
Author(s):  
Tz-Chuen Ju ◽  
Hui-Mei Chen ◽  
Jiun-Tsai Lin ◽  
Ching-Pang Chang ◽  
Wei-Cheng Chang ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Energy Homeostasis ◽  
Nuclear Translocation ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Adenosine Monophosphate ◽  
Cag Repeats ◽  
Nuclear Accumulation ◽  
Striatal Neurons

Adenosine monophosphate–activated protein kinase (AMPK) is a major energy sensor that maintains cellular energy homeostasis. Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. In this paper, we report that activation of the α1 isoform of AMPK (AMPK-α1) occurred in striatal neurons of humans and mice with HD. Overactivation of AMPK in the striatum caused brain atrophy, facilitated neuronal loss, and increased formation of Htt aggregates in a transgenic mouse model (R6/2) of HD. Such nuclear accumulation of AMPK-α1 was activity dependent. Prevention of nuclear translocation or inactivation of AMPK-α1 ameliorated cell death and down-regulation of Bcl2 caused by mutant Htt (mHtt). Conversely, enhanced expression of Bcl2 protected striatal cells from the toxicity evoked by mHtt and AMPK overactivation. These data demonstrate that aberrant activation of AMPK-α1 in the nuclei of striatal cells represents a new toxic pathway induced by mHtt.

scholarly journals Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease

2018 ◽  
Vol 10 (458) ◽  
pp. eaat7108 ◽  
Author(s):  
Lauren M. Byrne ◽  
Filipe B. Rodrigues ◽  
Eileanor B. Johnson ◽  
Peter A. Wijeratne ◽  
Enrico De Vita ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Mutant Huntingtin ◽  
Resonance Imaging ◽  
Neurofilament Light ◽  
Effective Strategies ◽  
Mutation Carriers ◽  
In Silico Modeling

Huntington’s disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the HTT gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging in premanifest and manifest HD mutation carriers. Among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all nonbiofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over 4 to 8 weeks showed that CSF mHTT, CSF NfL, and plasma NfL concentrations were highly stable within individuals. In our cohort, concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, whereas NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. In silico modeling indicated that mHTT and NfL concentrations in biofluids might be among the earliest detectable alterations in HD, and sample size prediction suggested that low participant numbers would be needed to incorporate these measures into clinical trials. These findings provide evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.

scholarly journals Protein kinase CK2 alpha prime and alpha-synuclein constitute a key regulatory pathway in Huntington’s disease

2020 ◽  
Author(s):  
Dahyun Yu ◽  
Nicole Zarate ◽  
Francesco Cuccu ◽  
Johnny S. Yue ◽  
Taylor G. Brown ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Kinase Ck2 ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Striatal Neurons ◽  
Kinase Ck2

SummaryHuntington’s Disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion in the HTT protein. This mutation causes HTT misfolding and aggregation, preferentially affecting neurons of the basal ganglia. Other aggregation-prone proteins like alpha-synuclein (α-syn), mostly associated with Parkinson’s disease (PD), has recently been involved in motor deficits in HD, but its mechanism of action is unknown. Here we showed that α-syn serine 129 phosphorylation (α-syn-pS129), a posttranslational modification linked to α-synucleinopathy, is highly phosphorylated in the brain of symptomatic zQ175 HD mice. We demonstrated that such phosphorylation is mediated by Protein Kinase CK2 alpha prime (CK2α’), which is preferentially induced in striatal neurons in HD. Knocking out one allele of CK2α’ in zQ175 mice decreased α-syn-pS129 in the striatum and ameliorated several HD-like symptoms including neuroinflammation, transcriptional alterations, excitatory synaptic transmission deficits and motor dysfunction. Our data suggests CK2α’-mediated synucleinopathy as a key molecular mechanism of neurodegeneration in HD.

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