Huntington's Disease and Tau

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This week, we would like to share several latest articles are related to Huntington's Disease and Tau.

Title: Histone deacetylase-6 modulates Tau function in Alzheimer's disease
Authors: Tazeen Qureshi, Subashchandrabose Chinnathambi
Type: Review Article
Highlights:
●HDAC6 interacts with Tau and demonstrates multiple effects on its aggregation.
●HDAC6 is potentially involved in Tau proteostasis through chaperone-mediated and/or aggresome-mediated autophagy.
●HDAC6 interacts with major cytoskeletal proteins and may promote cytoskeletal restructuring in neurons.
●The ZnF UBP domain of HDAC6 may be the resolution and solution to the controversial significance of HDAC6 in AD.
Abstract:
Alzheimer's disease (AD), one of the major tauopathies, is multifactorial with a massive demand for disease-modifying treatments rather than symptom management. An AD-affected neuron shows Tau depositions generated due to overload on the proteostasis machinery of the cell and/or abnormal post-translational modifications on Tau protein. Loss of memory or dementia is the most significant concern in AD, occurring due to the loss of neurons and the connections between them. In a healthy brain, neurons interact with the environment and each other through extensions and migratory structures. It can thus be safe to assume that Tau depositions affect these growth structures in neurons. A Histone Deacetylase, HDAC6, has shown elevated levels in AD while also demonstrating direct interaction with the Tau protein. HDAC6 interacts with multiple proteins in the cell and is possibly involved in various signalling pathways. Its deacetylase activity has been a point of controversy in AD; however other functional domains remain unexplored. This review highlights the beneficial potential of HDAC6 in AD in mediating both Tau proteostasis and cytoskeletal rewiring for the neuritic extensions through its Ubiquitin Binding domain (HDAC6 ZnF UBP).
Access this article: https://doi.org/10.1016/j.bbamcr.2022.119275

Title: SUMO-modifying Huntington's disease
Authors: Ericks S. Soares, Rui D. Prediger, Patricia S. Brocardo, Helena I. Cimarosti
Type: Mini Review
Abstract:
Small ubiquitin-like modifiers, SUMOs, are proteins that are conjugated to target substrates and regulate their functions in a post-translational modification called SUMOylation. In addition to its physiological roles, SUMOylation has been implicated in several neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases (HD). HD is a neurodegenerative monogenetic autosomal dominant disorder caused by a mutation in the CAG repeat of the huntingtin (htt) gene, which expresses a mutant Htt protein more susceptible to aggregation and toxicity. Besides Htt, other SUMO ligases, enzymes, mitochondrial and autophagic components are also important for the progression of the disease. Here we review the main aspects of Htt SUMOylation and its role in cellular processes involved in the pathogenesis of HD.
Access this article: https://doi.org/10.1016/j.ibneur.2022.03.002

Title: Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer's disease therapy
Authors: Chuanbin Yang, Chengfu Su, Ashok Iyaswamy, Senthil Kumar Krishnamoorthi, Zhou Zhu, Sichang Yang, Benjamin Chunkit Tong, Jia Liu, Sravan G. Sreenivasmurthy, Xinjie Guan, Yuxuan Kan, Aston Jiaxi Wu, Alexis Shiying Huang, Jieqiong Tan, Kingho Cheung, Juxian Song, Min Li
Type: Original Article
Abstract:
Alzheimer's disease (AD), characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates, is the most common neurodegenerative disorder with limited therapeutic agents. Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates, and transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Thus, small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy. Here, we found that celastrol, an active ingredient isolated from the root extracts of Tripterygium wilfordii (Lei Gong Teng in Chinese) enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains. Importantly, celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice, two commonly used AD animal models. Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol. Overall, our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models. Therefore, Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.
Access this article: https://doi.org/10.1016/j.apsb.2022.01.017

Title: Tauopathies: The Role of Tau in Cellular Crosstalk and Synaptic Dysfunctions
Authors: Marta Caamaño-Moreno, Ricardo Gargini
Type: Review Article
Highlights:
●The crosstalk between different cells is fundamental to understand the processes of cognitive dysfunction.
●The glial inclusions of tau play an important role in neurodegenerative diseases.
●Synaptic plasticity depends on the intact crosstalk between neurons and glia in the brain.
●Glia-related neuroinflammation plays a role in neurodegeneration.
●The Glia-tau-neuron triangle could be the promoter of the synapse loss in tauopathies.
Abstract:
Tauopathies are a group of neurodegenerative diseases among which are many of the most prevalent and with higher incidence worldwide, such as Alzheimer’s disease (AD). According to the World Health Organization, this set of diseases will continue to increase their incidence, affecting millions of people by 2050. All of them are characterized by aberrant aggregation of tau protein in neurons and glia that are distributed in different brain regions according to their susceptibility. Numerous studies reveal that synaptic regulation not only has a neuronal component, but glia plays a fundamental role in it beyond its neuroinflammatory role. Despite this, it has not been emphasized how the glial inclusions of tau in this cell type directly affect this and many other essential functions, whose alterations have been related to the development of tauopathies. In this way, this review shows how tau inclusions in glia influence the synaptic dysfunctions that result in the cognitive symptoms characteristic of tauopathies. Thus, the mechanisms affected by inclusions in neurons, astrocytes, and oligodendrocytes are unraveled.
Access this article: https://doi.org/10.1016/j.neuroscience.2022.02.034

Title: Cell models for Alzheimer's and Parkinson's disease: At the interface of biology and drug discovery
Authors: Sandra Cetin, Damijan Knez, Stanislav Gobec, Janko Kos, Anja Pišlar
Type: Review Article
Highlights:
●Treatments that effectively slow the progression of neurodegeneration are lacking.
●Cell-based models of neurodegeneration are pivotal in drug discovery projects.
●Phenotypic screening is useful approach to screen for novel therapeutic molecules.
●Functional assays of neuronal death can be used to screen therapeutic compounds.
Abstract:
Neurodegenerative diseases are severely debilitating conditions characterized primarily by progressive neuronal loss and impairment of the nervous system. Alzheimer’s and Parkinson’s diseases are the most common neurodegenerative disorders, and their impact is increasing as average life expectancy increases worldwide. Although the underlying mechanisms of both progressive diseases have been extensively studied, we still lack a comprehensive understanding of the molecular basis of both diseases. Current therapeutic options do not slow the progression of the diseases and only provide symptom relief. Cell models that resemble the characteristics of the disease in question are important in drug discovery projects because they provide information about the therapeutic benefits of drugs under development. Here, we review current in vitro cell models used to study the molecular basis of Alzheimer’s and Parkinson’s disease focusing on their potential for discovering of disease-modifying therapeutics to combat neurodegenerative diseases. We discuss phenotypic screening as an important approach for identifying novel therapeutic molecules. Advances in the development of cell-based assays for drug discovery are discussed, ranging from simple monoculture cell models to high-throughput three-dimensional cell models. Finally, we critically present the limitations of cell models and the caveats encountered in drug discovery to find effective treatment for neurodegenerative diseases.
Access this article: https://doi.org/10.1016/j.biopha.2022.112924

Title: Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder
Authors: C. Trujillo-Del Río, J. Tortajada-Pérez, A.P. Gómez-Escribano, F. Casterá, C. Peiró, J.M. Millán, M.J. Herrero, R.P. Vázquez-Manrique
Type: Review Article
Highlights:
●Huntington disease is a multi-system disorder and huntingtin is expressed ubiquitously.
●Metformin is a pleiotropic drug which may reach most tissues, and activates a range of targets beneficial to treat HD.
●Gut microbiota interplay with metformin substantially increases complexity of using this drug to treat HD.
●Studying targets of metformin, gut microbiota and using pharmacogenetics, may help design personalised medicine to treat HD.
Abstract:
Huntington disease (HD) is a neurodegenerative disorder produced by an expansion of CAG repeats in the HTT gene. Patients of HD show involuntary movements, cognitive decline and psychiatric impairment. People carrying abnormally long expansions of CAGs (more than 35 CAG repeats) produce mutant huntingtin (mHtt), which encodes tracks of polyglutamines (polyQs). These polyQs make the protein prone to aggregate and cause it to acquire a toxic gain of function. Principally affecting the frontal cortex and the striatum, mHtt disrupts many cellular functions. In addition, this protein is expressed ubiquitously, and some reports show that many other cell types are affected by the toxicity of mHtt. Several studies reported that metformin, a widely-used anti-diabetic drug, is neuroprotective in models of HD. Here, we provide a review of the benefits of this substance to treat HD. Metformin is a pleiotropic drug, modulating different targets such as AMPK, insulin signalling and many others. These molecules regulate autophagy, chaperone expression, and more, which in turn reduce mHtt toxicity. Moreover, metformin alters gut microbiome and its metabolic processes. The study of potential targets, interactions between the drug, host and microbiome, or genomic and pharmacogenomic approaches may allow us to design personalised medicine to treat HD.
Access this article: https://doi.org/10.1016/j.mad.2022.111670

Title: Environmental stimulation in Huntington disease patients and animal models
Authors: Arianna Novati, Huu Phuc Nguyen, Julia Schulze-Hentrich
Type: Review Article
Highlights:
●Environmental stimulation modulates Huntington disease (HD) onset and progression.
●Environmental stimulation in HD rodents affects pathology and neuroplasticity.
●The regulatory factors mediating environmental effects in HD are unknown.
●Epigenetic factors are key promising mediators of the environmental action in HD.
●HD preclinical studies should combine environmental stimulation and other therapies.
Abstract:
While Huntington disease (HD) is caused solely by a polyglutamine expansion in the huntingtin gene, environmental factors can influence HD onset and progression. Here, we review studies linking environment and HD in both humans and animal models. In HD patients, we find that: (i) an active lifestyle associates with both a delayed age at onset of HD and a decreased severity of symptoms, (ii) applying physical exercise and behavioral therapies in small cohorts of HD subjects indicate promising effects on the HD symptomatology, (iii) a diet rich in monounsaturated fatty acids and antioxidants correlates with reduced motor impairment, and treatments based on omega-3 fatty acids improves UHDRS motor scores, whereas (iv) increased cortisol levels associate with specific HD symptoms. In animal models, in line with the evidence in humans, physical exercise, environmental enrichment and different types of dietary intervention ameliorate or delay several HD phenotypes. In contrast, stress appears to be involved in the HD pathogenesis, and HD mice present increased stress sensitivity. Importantly, studies in animal models have uncovered several molecular factors mediating environmental effects on HD associated neuropathology. However, the influence of the environment on several key HD mechanisms as well as the underlying regulatory factors remain to be explored. Given the role of epigenetic factors and modifications in the interplay between environment and genes, the exploration of their role as mechanisms underlying the environmental action in HD is a promising avenue for both our fundamental understanding of the disease and as a potential for therapy.
Access this article: https://doi.org/10.1016/j.nbd.2022.105725