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Mitochondrial Dysfunction in Huntington Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Md. Hafiz Uddin, Marufa Rumman, Tasnuva Sarowar
HD is a dreadful neurodegenerative disease with characteristic cognitive behavioral features affecting 2.71 persons per 100,000 worldwide. The prevalence of HD can be as high as 15 persons per 100,000 which is observed in Western European population (Osellame, Blacker, and Duchen 2012; Dayalu and Albin 2015; Frank 2014; Sack 2010). Although HD is typically inherited, approximately 10% of the cases are due to a new mutation (Dayalu and Albin 2015). The disease is caused by an autosomal dominant mutation in huntingtin (HTT) gene (Milakovic and Johnson 2005). The pathogenesis of HD is initiated by neurodegeneration in the medium spiny neurons of striatum. Other parts of the brain, such as frontal and parietal cortices, are affected in the later stages of the disease (Sack 2010; Costa and Scorrano 2012). Gross pathology includes marked brain atrophy, which is more pronounced in the caudate nucleus and putamen, and large ventricular volumes (Sack 2010; Cepeda-Prado et al. 2012). In fact, positron emission tomography (PET) studies have shown changes in caudate, putamen, and cortex in both HD and presymptomatic HD individuals (Perez-De la Cruz and Carrillo-Mora 2010). The earliest signs of HD often are depression, mood changes, or psychosis. A suicidal tendency has also been noted in affected individuals. Poor attention and memory loss begin early and can progress slowly. The important recognizing feature is the involuntary and uncoordinated movement disorder accompanied by restlessness or “fidgeting.” The characteristics of chorea (Gk “dance”) become prominent over time (Sack 2010).
Neurotransmitters and Receptors in the Basal Ganglia
Published in W. R. Wayne Martin, Functional Imaging in Movement Disorders, 2019
The caudate/putamen itself contains several different neuronal types. The most abundant neuron is the medium spiny neuron which is thought to use gamma-aminobutyric acid (GABA) as its neurotransmitter.23 These neurons comprise from 70 to 90% of the neurons within the caudate/putamen and often contain one or more of a number of neuropeptides in addition to GABA.5,6,8 The medium spiny neurons project to the major output regions of the basal ganglia, which are discussed below. They also have a large number of recurrent axon collaterals that are distributed primarily within the dendritic field of the neuron.25,26 In addition to the medium spiny neurons, there are also small numbers of large cholinergic interneurons (large aspiny neurons)27 and small somatostatin/neuropeptide Y interneurons (small aspiny neurons).28,29
Animal models of Huntington’s disease and their applicability to novel drug discovery and development
Published in Expert Opinion on Drug Discovery, 2023
Shubham Upadhayay, Sumit Jamwal, Puneet Kumar
Huntington’s disease (HD) is a severe neurodegenerative disorder instigated by a mutation in the huntingtin (Htt) gene that leads to the production of mutant huntingtin protein (mHTT), whose aggregates degenerate the GABAergic medium spiny neurons (MSNs) in the basal ganglia, resulting in increased involuntary movements [1]. According to optimistic estimates, about 2.7 million people worldwide suffer from HD-like clinical manifestations, including jerking movements, fecal tenesmus, cognitive impairment, apathy, and difficulty in performing routine activities [2]. The key pathogenic processes involved in neuronal degeneration in HD include oxidative stress, mitochondrial dysfunction, apoptosis, neuroinflammation, transcriptional regulation, altered neurotransmitter signaling, and mitochondrial biogenesis [1,3]. The prevalence of HD increases day by day as a meta-analysis study of 2011 to 2022 suggests that the count of HD patients reaches to 4.88 per 100,000 patients when compared to the prevalence in 1985 to 2010, i.e. 2.71 per 100,000 patients, indicating that the incidence of HD gets doubled in 10 years [4]. Only two FDA-approved drugs (tetrabenazine and deutetrabenazine) are available in the market, which provides symptomatic relief with untoward side effects [5]. Therefore, there is an urgent need to discover newer therapies that could effectively help in the management of this disease.
Dyskinesia and Parkinson’s disease: animal model, drug targets, and agents in preclinical testing
Published in Expert Opinion on Therapeutic Targets, 2022
Valentina Cesaroni, Fabio Blandini, Silvia Cerri
Two relatively distinct pathways convey signals from the striatum through the basal ganglia: the direct pathway, originating from GABAergic striatal medium spiny neurons expressing dopamine D1 receptors and projecting monosynaptically to globus pallidus pars interna (GPi)/substantia nigra pars reticulata (SNpr); and the indirect pathway, originating from GABAergic striatal medium spiny neurons expressing D2 receptors and influencing GPi/SNpr via the globus pallidus pars externa (GPe) and the subthalamic nucleus (STN). These two pathways have opposite net effects on thalamic target structures: excitation of the direct pathway causes activation of thalamic neurons, whereas excitation of the indirect pathway leads to inhibition of thalamic neurons. Findings in dopamine-depleted animals have shown that a major imbalance between the activity of the direct and indirect striatal pathways is probably responsible for dyskinetic movements induced by chronic L-DOPA administration. In particular, a reduction of firing rate and a modified patterns of discharge of internal pallidus neurons, associated with a decreased firing rate and irregular firing patterns of subthalamic neurons, have been observed in LID. Moreover, mechanisms such as the non-physiological stimulation of dopamine-deprived receptors and abnormal synaptic plasticity at corticostriatal synapses seem to be equally involved in LID pathophysiology [12].
The CB2 cannabinoid receptor as a therapeutic target in the central nervous system
Published in Expert Opinion on Therapeutic Targets, 2021
David Cabañero, Elena Martín-García, Rafael Maldonado
Huntington’s disease is an autosomal dominant neurodegenerative disorder characterized by involuntary and excessive movements named chorea in addition to cognitive and psychiatric symptoms [103]. Huntington’s disease causes the death of dopaminergic neurons in the globus pallidus, and no disease-modifying therapies that cure Huntington’s disease are available. Similar to other neurodegenerative disorders, CB2r expression is enhanced in postmortem brains from patients with Huntington’s disease and in experimental animal models [104]. Notably, increased CB2r expression in active striatal microglia of Huntington’s disease patients is a prominent sign of inflammatory response from the early phases of the illness [105]. CB2r agonists can prevent motor impairment and the loss of medium spiny neurons in animal models of Huntington’s disease (R6/1 mice) [106]. In addition, enhanced microglial activation is an early pathogenic step correlated to disease development and the upregulation of microglial CB2rs supports a crucial role for the endocannabinoid system in the pathogenesis of Huntington’s disease [107]. However, no clinical trials have been yet designed to target the CB2r in Huntington’s disease. Thus, the endocannabinoid system via CB2r might constitute an ideal approach for regulating Huntington’s disease and other neurodegenerative disorders with significant excitotoxicity components.