The Neurodevelopmental Hypothesis of Huntington’s Disease

Plas, Ellen van der; Schultz, Jordan L.; Nopoulos, Peg

doi:10.3233/jhd-200394

Cited by 40 publications

(26 citation statements)

References 60 publications

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“…The pathophysiology of neurodegenerative diseases is complex, and many possible pathways have been proposed as therapeutic targets to slow down disease progression and preserve neurological functions of the affected individuals. In general, the development of Alzheimer's, Parkinson's and Huntington's diseases is associated with pathological accumulation of specific proteins in vital brain centres responsible for cognition, memory, motor activity and other essential neurological processes [154,155].…”

Section: Ipa Has a Protective Role In Neurodegenerative Disease Modelsmentioning

confidence: 99%

Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease

Konopelski

Mogilnicka

2022

IJMS

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Actions of symbiotic gut microbiota are in dynamic balance with the host’s organism to maintain homeostasis. Many different factors have an impact on this relationship, including bacterial metabolites. Several substrates for their synthesis have been established, including tryptophan, an exogenous amino acid. Many biological processes are influenced by the action of tryptophan and its endogenous metabolites, serotonin, and melatonin. Recent research findings also provide evidence that gut bacteria-derived metabolites of tryptophan share the biological effects of their precursor. Thus, this review aims to investigate the biological actions of indole-3-propionic acid (IPA), a gut microbiota-derived metabolite of tryptophan. We searched PUBMED and Google Scholar databases to identify pre-clinical and clinical studies evaluating the impact of IPA on the health and pathophysiology of the immune, nervous, gastrointestinal and cardiovascular system in mammals. IPA exhibits a similar impact on the energetic balance and cardiovascular system to its precursor, tryptophan. Additionally, IPA has a positive impact on a cellular level, by preventing oxidative stress injury, lipoperoxidation and inhibiting synthesis of proinflammatory cytokines. Its synthesis can be diminished in the presence of different risk factors of atherosclerosis. On the other hand, protective factors, such as the introduction of a Mediterranean diet, tend to increase its plasma concentration. IPA seems to be a promising new target, linking gut health with the cardiovascular system.

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Section: Ipa Has a Protective Role In Neurodegenerative Disease Modelsmentioning

confidence: 99%

Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease

Konopelski

Mogilnicka

2022

IJMS

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“…In HD patients, mutant huntingtin is expressed throughout life, including during embryogenesis (Saudou and Humbert, 2016). In line with this, the expression of mutant huntingtin has been shown to affect not only adult neuronal function, leading to neurodegeneration, but also neurodevelopment including neuronal differentiation and establishment of connectivity through neurite outgrowth (Conforti et al, 2018;Barnat et al, 2020;van der Plas et al, 2020). Intriguingly, mouse models expressing mutant huntingtin solely during embryonic and early development develop HD-like symptoms (Molero et al, 2016).…”

Section: Huntington's Diseasementioning

confidence: 90%

Nicotinamide Adenine Dinucleotide Phosphate Oxidases Are Everywhere in Brain Disease, but Not in Huntington’s Disease?

Villegas

Nørremølle

Freude

et al. 2021

Front. Aging Neurosci.

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Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by neuronal loss and tissue atrophy mainly in the striatum and cortex. In the early stages of the disease, impairment of neuronal function, synaptic dysfunction and white matter loss precedes neuronal death itself. Relative to other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease and Amyotrophic Lateral Sclerosis, where the effects of either microglia or NADPH oxidases (NOXs) are recognized as important contributors to disease pathogenesis and progression, there is a pronounced lack of information in HD. This information void contrasts with evidence from human HD patients where blood monocytes and microglia are activated well before HD clinical symptoms (PET scans), and the clear signs of oxidative stress and inflammation in post mortem HD brain. Habitually, NOX activity and oxidative stress in the central nervous system (CNS) are equated with microglia, but research of the last two decades has carved out important roles for NOX enzyme function in neurons. Here, we will convey recent information about the function of NOX enzymes in neurons, and contemplate on putative roles of neuronal NOX in HD. We will focus on NOX-produced reactive oxygen species (ROS) as redox signaling molecules in/among neurons, and the specific roles of NOXs in important processes such as neurogenesis and lineage specification, neurite outgrowth and growth cone dynamics, and synaptic plasticity where NMDAR-dependent signaling, and long-term depression/potentiation are redox-regulated phenomena. HD animal models and induced pluripotent stem cell (iPSC) studies have made it clear that the very same physiological processes are also affected in HD, and we will speculate on possible roles for NOX in the pathogenesis and development of disease. Finally, we also take into account the limited information on microglia in HD and relate this to any contribution of NOX enzymes.

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“…In addition, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia (Blumcke and others 2011), which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD (Cepeda and others 2019; Cummings and others 2009). These studies provide strong evidence that HD is not only a neurodegenerative disorder but also a disease of faulty neurodevelopment (Barnat and others 2020; Blockx and others 2012; Wiatr and others 2018), particularly expressed in the juvenile form of HD (Tereshchenko and others 2015; van der Plas and others 2020).…”

Section: Abnormal Cortical Brain Development In Hdmentioning

confidence: 91%

Synaptic Dysfunction in Huntington’s Disease: Lessons from Genetic Animal Models

Cepeda

Levine

2020

Neuroscientist

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The understanding of the functional and structural changes occurring in the cerebral cortex and basal ganglia in Huntington’s disease (HD) has benefited considerably from the generation of genetic animal models. Most studies of synaptic alterations in HD models have focused on the striatum, but a more complete picture of synaptic dysfunction in the cortico-basal ganglia-cortical loop is emerging. Here, we provide a review and analysis of current developments in the study of synaptic alterations in these areas using HD rodent models. Recent evidence indicates that cortical maldevelopment plays a role in synaptic dysfunction along the corticostriatal pathway that may have its roots in the way mutant huntingtin interacts with synaptic proteins. Furthermore, a progressive disconnection in the corticostriatal pathway leads to abnormal function engaging extrasynaptic N-methyl-D-aspartate glutamate receptors that contribute to eventual cell degeneration. In addition, biphasic increases followed by decreases in glutamate and dopamine release in the striatum could explain contrasting symptomatology in early and late stages of the disease. Changes in striatal output regions also are beginning to be examined. Finally, we highlight some therapeutic avenues aimed at rescuing synaptic dysfunction.

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The Neurodevelopmental Hypothesis of Huntington’s Disease

Cited by 40 publications

References 60 publications

Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease

Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease

Nicotinamide Adenine Dinucleotide Phosphate Oxidases Are Everywhere in Brain Disease, but Not in Huntington’s Disease?

Synaptic Dysfunction in Huntington’s Disease: Lessons from Genetic Animal Models

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