Huntington's disease: From basic science to therapeutics

Huntingtons disease treatments In 1872, George Huntington, an American physician who at the time was only 22 years old, published a short communication in the “Medical and Surgical Reporter” (Philadelphia) describing a hereditary form of chorea (uncontrollable dance-like movements similar to St. Vitus dance). As a young boy, George had accompanied his father in his visits to families in East Hampton, New York, who were affected by the dreaded disease and noticed that if the parents presented with the disease, their progeny had a great chance of acquiring it. These observations led him to write the above-noted first description of the disease, which ultimately was named after him. In 1993, the gene mutation causing Huntington's disease (HD) was discovered thanks to the impetus of Dr. Nancy Wexler (Columbia University) and collaborators.1 It consists of an elongation of CAG (coding for glutamine) repeats in a previously unknown gene located in the short arm of chromosome 4. When the number of CAG repeats exceeds 39, the disease will inexorably occur at some point in life. HD is a devastating, incurable neurodegenerative disease. Its prevalence is relatively high in Western European nations, Venezuela, the United States, Canada, and Oceania (5-10/100 000) but very low in Asian and most African countries (0.1-0.5/100 000). Although victims of the disease are thus relatively rare, the number of people at risk is significantly higher, emphasizing the need for finding new treatments to alleviate symptoms and improve the quality of life for patients suffering from HD. The hallmark histopathology of HD is cell degeneration in striatum and cerebral cortex, which explains the emergence of motor (chorea), cognitive, and psychiatric symptoms. The probable causes of cell death are still unknown, but significant strides have been made in the past few years to understand disease mechanisms. Such advances have been made possible in part by the generation of genetic animal models of HD. Before the advent of such models, excitotoxic models (eg, intrastriatal injection of quinolinic acid) were the only tools for mechanistic studies and were based on the idea that excessive glutamate release from corticostriatal terminals or heightened sensitivity of glutamate receptors in striatal neurons was the principal cause of cell death.2 The excitotoxic models, although certainly possessing some heuristic value, proved to be simplistic and to have important shortcomings, notably in that they did not allow examination of disease progression. Although also imperfect, genetic animal models have provided a vast number of mechanistic insights and have emphasized the fact that functional alterations, more than cell death, can explain a variety of HD symptoms.3 In particular, synaptic disconnection and miscommunication between basal ganglia structures and the cerebral cortex appear to play a crucial role. The R6/2 transgenic mouse model, created in the laboratory of Dr. Gillian Bates (then at King's College London) just 3 years after the discovery of the gene mutation,4 has been instrumental in the exploration of new therapies for HD and the gold standard for drug testing. Since then, numerous animal models have been created that allowed further insights into disease mechanisms and progression. Although no model can reproduce yet the whole gamut of human HD symptoms, animal models represent an invaluable source of knowledge and probably the only way to develop a real cure. The present Special Issue (SI) on HD is a small compendium of recent advances arising from the utilization of animal and cellular models for better understanding of disease mechanisms and for discovering new potential treatments. The authors are well-renowned leaders in their respective fields, and each one has provided either original data or detailed reviews. The 9 articles included in this issue can be considered a snapshot of the current status of HD research using those models. In no way does it aim to be a comprehensive overview of the vast amount of research presently being conducted in the HD field. However, we hope that this SI will attract the attention of investigators working on HD and other neurodegenerative diseases that may share common mechanisms. Although the functions of the normal huntingtin protein are still unclear, there is substantial evidence that, among others, it plays a key role in proper brain development, transcriptional regulation, vesicle transport, and synaptic transmission.5, 6 From a systems perspective, it is of great interest that communication along the cortico-basal ganglia-thalamocortical loop is disrupted, lending support to the idea that HD is, above all, a synaptopathy.7 Disrupted connectivity is best exemplified in Anton Reiner's (University of Tennessee) review examining striatal neuron inputs and outputs in HD8 (pp. 250–280). Professor Reiner is a world-renowned authority in the field of HD and one of the discoverers of the increased vulnerability of enkephalin-containing striatal projection neurons (SPNs) constituting the indirect pathway. In particular, he is interested in anatomical changes occurring in patients and in animal models during HD progression. In his detailed review, Professor Reiner dissects the topography and chronology of connectivity changes occurring in HD. From early loss of cortical and thalamic inputs to striatum to late disruption of direct pathway SPNs, he is able to explain the changing patterns of motor dysfunction in HD patients. Abnormalities in glutamate release and/or glutamate receptor sensitivity have long been invoked to explain striatal cell death in HD. Although probably not exclusive, anatomical and physiological data support glutamate involvement. George Rebec (Indiana University) has been studying corticostriatal communication and how glutamate transport in the corticostriatal pathway is altered in HD animal models9 (pp. 281–291). Using a wide array of techniques including in vivo electrophysiological recordings, measurement of glutamate release, and computational modeling Professor Rebec and his team have demonstrated important changes in striatal and cortical neuron firing patterns, as well as dysregulation of dynamic changes in extracellular glutamate and ascorbate. By demonstrating deficits in astrocyte-mediated glutamate transport in the striatum, he has paved the way for new ideas to treat HD. He has shown that increased expression of glutamate transport proteins restores glutamate and ascorbate homeostasis in striatum while normalizing striatal neuronal activity and improving behavioral signs. However, in HD not only glutamate transmission goes awry. Dysregulation of glutamate release along the corticostriatal pathway triggers compensatory mechanisms to prevent cell damage. The function of GABA, the main inhibitory neurotransmitter in the brain, also is altered in HD. Upregulation of phasic GABA release in striatum, as well as deficits in tonic GABA, has been demonstrated in mouse models. Maurice Garret (Université de Bordeaux) is an expert on GABA receptor structure and function in the brain. Recently, he has focused his attention on uncovering alterations of GABA receptors in animal models. He demonstrated, beyond doubt, that glutamate and dopamine are not the only neurotransmitters affected by the malady, as the GABA system also is deeply altered. In addition, GABA is the main neurotransmitter used by SPNs of both direct and indirect pathways. Thus, any changes in GABA function occurring in striatum will have an effect on key output regions including the external globus pallidus and the substantia nigra pars reticulata. In his insightful review10 (pp. 292–300), Dr. Garret examines specific changes in GABAA receptor subunits in different basal ganglia regions and highlights potential therapeutic avenues by targeting selective GABAA receptor subunits to treat nonmotor symptoms such as sleep disturbances commonly observed in HD. The laboratory of Lynn Raymond (University of British Columbia, Vancouver) is well known for its contributions to our understanding of the role that glutamate extrasynaptic NMDA receptors play in excitotoxicity. Deleterious effects are likely mediated by dysregulation of calcium influx and handling in different cell compartments. Dr. Raymond and her collaborators James P. Mackay and Wissam B. Nassrallah discuss how abnormal calcium handling can lead to neuronal degeneration11 (pp. 301–310). As many alterations observed in HD animal models occur very early in development, they wonder whether changes are a primary cause or the result of compensatory mechanisms. This is a provocative idea emphasizing the capabilities of the brain to repair itself. Their review also highlights possible therapies focused on restoring calcium homeostasis. Calcium influx, either via NMDA receptors or voltage-gated and store-operated channels, is not the only process affected in HD. Potassium channels also play an important role as they are involved in myriad of cellular processes, most of them designed to prevent neuronal hyperexcitability. Potassium channel dysfunction was first suspected by studies showing that SPNs are more depolarized in HD mouse models, pointing to decreased inward rectification due to loss of Kir channel expression. Working in Baljit Khakh's laboratory (University of California Los Angeles), Xiaoping Tong (presently a Professor at Shanghai Jiao Tong University School of Medicine) discovered that astrocytic Kir4.1 channels were deficient in HD mouse models. This deficit was accompanied by increased extracellular potassium, which in turn could explain depolarized resting membrane potentials of affected SPNs. Further, upregulation of Kir4.1 channels ameliorated the HD phenotype. In their contribution to the SI12 (pp. 311–318), Professor Tong and collaborators review evidence summarizing recent progress on the function of neuronal and astrocytic potassium channels and their involvement in HD pathology using animal models. They also illustrate how targeting potassium channels can be used for the treatment of HD. The altered interplay between neurotransmitters and channels explains many of the molecular cascades leading to neurodegeneration in HD. But this is not, by any stretch of the imagination, the whole story. Cellular energy metabolism is deeply disturbed in HD. In particular, inefficient use of lactate by HD neurons contributes to metabolic failure. Maité A. Castro (Universidad Austral de Chile), an expert in cellular energy metabolism, and colleagues demonstrate that HD cells exhibit decreased expression of the neuronal glucose transporter GLUT3, which could be the cause of insufficient energy supply13 (pp. 343–352). Further, stimulation of lactate uptake by ascorbic acid could be restored by overexpressing GLUT3. Again this opens new avenues for HD treatment. Another potential avenue targets transcriptional dysregulation, a major cause of HD pathology. Francesca Fusco (Fondazione Santa Lucia, Rome) and Antonella Cardinale review recent neuroprotective strategies via phosphodiesterase (PDE) inhibition and consequent upregulation of cyclic nucleotide signaling in HD14 (pp. 319–328). They argue that, since mutant huntingtin alters cAMP response element-binding protein (CREB), which in turn promotes transcription of brain-derived neurotrophic factor (BDNF), strategies aimed at increasing CREB transcription could have neuroprotective effects in HD animals. As PDEs are enzymes that catabolize cAMP and/or cGMP in the cell, their inhibition could be beneficial. Also highlighting the beneficial effects of neurotrophic factors, Elizabeth Hernández-Echeagaray (Universidad Nacional Autónoma de México) and colleagues examine the role of neurotrophin-3 (NT-3) in neuroprotection and synaptic plasticity in the striatum of an animal model of HD15 (pp. 353–363). They convincingly demonstrate that normal synaptic plasticity in the corticostriatal pathway is aberrant in HD model mice but it can be restored by administration of NT-3. One of the most challenging aspects of HD research relating to therapies is whether cell loss can be prevented or cells can be replaced. In human HD and, to a lesser degree, in genetic animal models, striatal and cortical cell loss is massive. Fortunately, regenerative medicine is becoming a reality and specific cell types may be able to be replaced using stem cells that can be induced to adopt particular phenotypes. Recent studies demonstrate that cells implanted in the brain of HD model mice can survive and differentiate. Notably, most studies demonstrate clear benefits on HD symptoms with some showing a possible mechanism of action that includes the release of neurotrophic factors such as BDNF. Sandra M. Holley (University of California Los Angeles, UCLA), working in the Cepeda-Levine laboratory, and associates at the University of California Davis (UCD) and at the University of California Irvine (UCI) review the use of stem cells in HD animal models16 (pp. 329–342). In their California Institute for Regenerative Medicine (CIRM)-funded studies, they showed that human-derived neural stem cells implanted in HD mice can protect or repair damaged tissue, delay disease progression, decrease pathologies, and increase production of neurotrophic molecules. In this SI, they also provide a more detailed electrophysiological characterization of human-derived neural stem cells implanted in HD mice. We would like to thank all the contributors who took time from their busy schedules to write comprehensive reviews or high-quality original papers that will certainly help the neuroscience community in general and the HD field in particular. Finally, we would like to thank CNSNT and its Editor-in-Chief, Ding-Feng Su, as well as its Managing Editor, Buddy Zhou, for encouraging the compilation of this SI on HD. Without their input and guidance, this SI would not have been possible.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.