Abstract:Cognitive dysfunction is an early clinical hallmark of Huntington's disease (HD) preceding the appearance of motor symptoms by several years. Neuronal dysfunction and altered corticostriatal connectivity have been postulated to be fundamental to explain these early disturbances. However, no treatments to attenuate cognitive changes have been successful: the reason may rely on the idea that the temporal sequence of pathological changes is as critical as the changes per se when new therapies are in development. … Show more
“…5b). These results, along with previous data showing no deficits of KI mice in the fixed rotarod at six months of age 40 , indicate that the results obtained with the accelerating rotarod task were due to motor learning and not motor coordination deficits. Overall, these findings demonstrate that impaired ability to learn new corticostriatal-dependent motor skills can be prevented in KI mice by early treatment with RGFP966.Figure 5RGFP966 treatment prevents impairment of motor learning in HD mice.…”
Huntington’s disease (HD) is a neurodegenerative disorder whose major symptoms include progressive motor and cognitive dysfunction. Cognitive decline is a critical quality of life concern for HD patients and families. The enzyme histone deacetylase 3 (HDAC3) appears to be important in HD pathology by negatively regulating genes involved in cognitive functions. Furthermore, HDAC3 has been implicated in the aberrant transcriptional patterns that help cause disease symptoms in HD mice. HDAC3 also helps fuel CAG repeat expansions in human cells, suggesting that HDAC3 may power striatal expansions in the HTT gene thought to drive disease progression. This multifaceted role suggests that early HDAC3 inhibition offers an attractive mechanism to prevent HD cognitive decline and to suppress striatal expansions. This hypothesis was investigated by treating HdhQ111 knock-in mice with the HDAC3-selective inhibitor RGFP966. Chronic early treatment prevented long-term memory impairments and normalized specific memory-related gene expression in hippocampus. Additionally, RGFP966 prevented corticostriatal-dependent motor learning deficits, significantly suppressed striatal CAG repeat expansions, partially rescued striatal protein marker expression and reduced accumulation of mutant huntingtin oligomeric forms. These novel results highlight RGFP966 as an appealing multiple-benefit therapy in HD that concurrently prevents cognitive decline and suppresses striatal CAG repeat expansions.
“…5b). These results, along with previous data showing no deficits of KI mice in the fixed rotarod at six months of age 40 , indicate that the results obtained with the accelerating rotarod task were due to motor learning and not motor coordination deficits. Overall, these findings demonstrate that impaired ability to learn new corticostriatal-dependent motor skills can be prevented in KI mice by early treatment with RGFP966.Figure 5RGFP966 treatment prevents impairment of motor learning in HD mice.…”
Huntington’s disease (HD) is a neurodegenerative disorder whose major symptoms include progressive motor and cognitive dysfunction. Cognitive decline is a critical quality of life concern for HD patients and families. The enzyme histone deacetylase 3 (HDAC3) appears to be important in HD pathology by negatively regulating genes involved in cognitive functions. Furthermore, HDAC3 has been implicated in the aberrant transcriptional patterns that help cause disease symptoms in HD mice. HDAC3 also helps fuel CAG repeat expansions in human cells, suggesting that HDAC3 may power striatal expansions in the HTT gene thought to drive disease progression. This multifaceted role suggests that early HDAC3 inhibition offers an attractive mechanism to prevent HD cognitive decline and to suppress striatal expansions. This hypothesis was investigated by treating HdhQ111 knock-in mice with the HDAC3-selective inhibitor RGFP966. Chronic early treatment prevented long-term memory impairments and normalized specific memory-related gene expression in hippocampus. Additionally, RGFP966 prevented corticostriatal-dependent motor learning deficits, significantly suppressed striatal CAG repeat expansions, partially rescued striatal protein marker expression and reduced accumulation of mutant huntingtin oligomeric forms. These novel results highlight RGFP966 as an appealing multiple-benefit therapy in HD that concurrently prevents cognitive decline and suppresses striatal CAG repeat expansions.
“…Without these mechanisms, neurons within various brain regions may become over-or under-connected to an extent which would interfere with their forming new connections, or strengthening or weakening existing ones (Watt and Desai, 2010); this could result in impairment of functions such as learning, memory and behavioural flexibility, which is characteristic of the cognitive symptoms of HD (Lawrence et al, 1996;Pouladi et al, 2013). This idea is supported by the association between decreased cortical expression of Kalirin-7, a guanine-nucleotide exchange factor involved in maintenance of dendritic spines, and development of a cognitive phenotype in HD model mice (Puigdell ıvol et al, 2015). If indeed impaired HSP contributes to cognitive deficits in HD, then treatment with pridopidine may provide additional benefits in ameliorating such symptoms, since it restores HSP at glutamatergic cortical synapses in cultures from HD mice (Smith-Dijak et al, 2019).…”
Section: Plasticity At Glutamatergic Synapsesmentioning
Huntington disease (HD) is an inherited neurodegenerative disorder caused by an expansion of the CAG repeat region in the first exon of the huntingtin gene. Neurodegeneration, which begins in the striatum and then spreads to other brain areas, is preceded by dysfunction in multiple aspects of neurotransmission across a variety of brain areas. This review will provide an overview of the neurochemical mediators and modulators of synaptic transmission that are disrupted in HD. This includes classical neurotransmitters like glutamate and gamma‐aminobutyric acid, modulators such as dopamine, adenosine and endocannabinoids, and molecules like brain‐derived neurotrophic factor which affect neurotransmission in a more indirect manner. Alterations in the functioning of these signaling pathways can occur across multiple brain regions such as striatum, cortex and hippocampus, and affect transmission and plasticity at the synapses within these regions, which may ultimately change behaviour and contribute to the pathophysiology of HD. The current state of knowledge in this area has already yielded useful information about the causes of synaptic dysfunction and selective cell death. A full understanding of the mechanisms and consequences of disruptions in synaptic function and plasticity will lend insight into the development of the symptoms of HD, and potential drug targets for ameliorating them.
“…These synaptic alterations have been suggested as contributing to cognitive symptoms in both HD patients and animal models (166,197,304,313). Supporting the hypothesis that loss of Kalirin-7 in the cortex of young HD mice could be associated with the early loss of excitatory synapses in HD, Kalirin-7 overexpression restores the number of cortical glutamatergic synapses in mature cultured HD cortical neurons (239). Supporting the hypothesis that loss of Kalirin-7 in the cortex of young HD mice could be associated with the early loss of excitatory synapses in HD, Kalirin-7 overexpression restores the number of cortical glutamatergic synapses in mature cultured HD cortical neurons (239).…”
“…In this context, there is an early and specific reduction in cortical Kalirin-7 levels in HD mice, paralleled by early cortical dendritic spine alteration, impaired corticostriatal LTP and cognitive deficits (239). In this context, there is an early and specific reduction in cortical Kalirin-7 levels in HD mice, paralleled by early cortical dendritic spine alteration, impaired corticostriatal LTP and cognitive deficits (239).…”
Section: Therapeutic Strategiesmentioning
confidence: 99%
“…Interestingly, Kalirin interacts with huntingtin-associated protein 1 (55), and alterations in excitatory synapses occur at early disease stages in HD mouse models (47, 79,172). In a recent study, and following a broad analysis of synaptic-related proteins such as NMDA (GluN1 and GluN2B) and AMPA (GluA1) receptor subunits, presynaptic (VGlut1 and synaptophysin) and postsynaptic (Kalirin-7, PSD95, Shank3 and CaMKII) scaffolding and signaling proteins, only Kalirin-7 showed an early and specific reduction in the cortex of Hdh Q7/Q111 and R6/1 mice, which correlates with cortical dendritic spine alteration, impaired corticostriatal synaptic plasticity and motor and procedural learning behavioral deficits in 2-and 6-month-old Hdh Q7/Q111 mice (239). In a recent study, and following a broad analysis of synaptic-related proteins such as NMDA (GluN1 and GluN2B) and AMPA (GluA1) receptor subunits, presynaptic (VGlut1 and synaptophysin) and postsynaptic (Kalirin-7, PSD95, Shank3 and CaMKII) scaffolding and signaling proteins, only Kalirin-7 showed an early and specific reduction in the cortex of Hdh Q7/Q111 and R6/1 mice, which correlates with cortical dendritic spine alteration, impaired corticostriatal synaptic plasticity and motor and procedural learning behavioral deficits in 2-and 6-month-old Hdh Q7/Q111 mice (239).…”
One of the main focuses in Huntington's disease (HD) research, as well as in most neurodegenerative diseases, is the development of new therapeutic strategies, as currently there is no treatment to delay or prevent the progression of the disease. Neuronal dysfunction and neuronal death in HD are caused by a combination of interrelated pathogenic processes that lead to motor, cognitive and psychiatric symptoms. Understanding how mutant huntingtin impacts on a plethora of cellular functions could help to identify new molecular targets. Although HD has been classically classified as a neurodegenerative disease affecting voluntary movement, lately cognitive dysfunction is receiving increased attention as it is very invalidating for patients. Thus, an ambitious goal in HD research is to find altered molecular mechanisms that contribute to cognitive decline. In this review, we have focused on those findings related to corticostriatal and hippocampal cognitive dysfunction in HD, as well as on the underlying molecular mechanisms, which constitute potential therapeutic targets. These include alterations in synaptic plasticity, transcriptional machinery and neurotrophic and neurotransmitter signaling.
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