Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington’s disease

Clifford, J.; Drago, John; Natoli, Anthony; Wong, J; Kinsella, Anthony; Waddington, John L.; Vaddadi, Krishna S

doi:10.1016/s0306-4522(01)00409-2

Cited by 106 publications

(47 citation statements)

References 27 publications

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“…Stereological analysis provides clear evidence that cell death occurred, whereas Drd1a and Drd2 in situ hybridization data confirm that cell death is indeed restricted to the Drd1aϩ cell compartment. Detailed behavioral analyses of MUT mice revealed a phenotype, elements of which are observed in other models of HD (15,16,23). We demonstrate that primary loss of a Drd1aϩ subpopulation can produce a tail suspension-induced hindlimb dystonic phenotype, locomotor hyperactivity, and significant changes in oral behavioral topographies.…”

Section: Discussionmentioning

confidence: 56%

“…No statistically significant differences were found in gait analysis or rotarod testing in MUT mice examined at 10-11 or 17-21 wk (SI Text). Separate cohorts of WT and MUT animals were assessed at two different age ranges by using a standardized ethological assay (22)(23)(24). At 6-9 wk, there was an increase in total rearing and a decrease in sifting and chewing (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Abnormalities in oral behavioral topographies and hyperactivity may explain the persistent weight differences seen in MUT mice. The ethogram was assessed in the R6/1 line of HD transgenic mice (23), and delayed onset decreases were identified in sifting and chewing. Speech and swallowing disturbances occur in HD, and motor impersistence on tongue protrusion is a classic physical sign in HD that differentiates HD from other disorders, such as tardive dyskinesia (10).…”

Section: Discussionmentioning

confidence: 99%

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Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

Gantois

Fang

Jiang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor (Drd1a)؉ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P, and dynorphin expression is progressively lost, whereas D2 dopamine receptor (Drd2) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electrographically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in the oral behaviors of sifting and chewing. In line with the limbic seizure profile, cell loss, astrogliosis, microgliosis, and down-regulated dynorphin expression were seen in the hippocampal dentate gyrus. This study specifically implicates Drd1a؉ cell loss with tail suspension hindlimb dystonia, hyperactivity, and abnormal oral function. The latter may relate to the speech and swallowing disturbances and the classic sign of tongueprotrusion motor impersistence observed in Huntington's disease. In addition, the findings of this study support the notion that Drd1a and Drd2 are segregated on striatal projection neurons. striatum ͉ Cre ͉ Huntington's disease T he nigrostriatal pathway projects from the midbrain substantia nigra pars compacta to innervate the dorsal striatum. Dopamine is released from dopaminergic terminals in the striatum to regulate motor activity and eating behavior (1). Early studies suggested that dopamine D1 (Drd1a) and D2 receptors (Drd2) are segregated on striatal projection neurons; the Drd1a is expressed on substance P and dynorphin-positive striatal neurons, which project directly to the substantia nigra pars reticulata/entopeduncular complex (known as the direct pathway), whereas Drd2 is preferentially expressed on enkephalin-positive striatopallidal projecting neurons (2). Neurons within the globus pallidus then project to the subthalamic nucleus, which in turn relays to the substantia nigra pars reticulata/entopeduncular complex (known as the indirect pathway). Dopamine also modulates the activity of glutamatergic corticostriatal input on striatal projection neurons.Idiopathic Parkinson's disease is characterized by the death of dopaminergic neurons; however, rare Parkinsonian syndromes have been identified in which the defect is associated with cell death in the dopamine-responsive neurons in the striatum (3-6). Huntington's disease (HD) (7-10), a neurodegenerative condition with motor, cognitive, and psychiatric disturbances, also involves death of dopamine receptor-expressing striatal projection neurons. Several ...

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Section: Discussionmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

Gantois

Fang

Jiang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, this treatment seemed to increase the survival of R6/1 mice (within the 43-week period of the study, the mortality appeared to decrease from 42% in the placebo-treated mice to 15% in the animals treated with essential fatty acids). However, the combination of essential fatty acids had no significant effect on the loss of body weight, and on the decreased expression of DA D1 and D2 receptors, suggesting that the fatty acids do not act at the level of the transcriptional abnormalities observed in these mice (Clifford et al, 2002). Systemic administration of α-lipoic acid (starting at 4 weeks of age) has also been shown to significantly improve the survival of R6/2 mice, although no effect on body weight was observed (Andreassen et al, 2001b).…”

Section: Antioxidantsmentioning

confidence: 89%

“…In one study, the diet of R6/1 mice was supplemented with several essential fatty acids (linoleic acid, γ-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, α-lipoic acid, d-α-tocopherol acetate) from conception and throughout adulthood (Clifford et al, 2002). The essential fatty acids linoleic acid and γ-linolenic acid are crucial for the regulation of membrane proteins and constitute central components in several neuronal signaling pathways, whereas α-lipoic acid (discussed below) and α-tocopherol (vitamin E) are antioxidant compounds.…”

Section: Antioxidantsmentioning

confidence: 99%

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Gil

Rego

2009

Brain Research Reviews

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HD gene that results in cortical and striatal degeneration, and mutant huntingtin aggregation. Current treatments are unsatisfactory. R6 transgenic mice replicate many features of the human condition, show early onset of symptoms and fast disease progression, being one of the most used models for therapy screening. Here we review the therapies that have been tested in these mice: environmental enrichment, inhibition of histone deacetylation and methylation, inhibition of misfolding and oligomerization, transglutaminase inhibition, rescue of metabolic impairment, amelioration of the diabetic phenotype, use of antioxidants, inhibition of excitotoxicity, caspase inhibition, transplantation, genetic manipulations, and restoration of neurogenesis. Although many of these treatments were beneficial in R6 mice, they may not be as effective in HD patients, and thus the search for a combination of therapies that will rescue the human condition continues.

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Lipids in the Treatment of Neurodegenerative Diseases

Lange

2020

Bailey's Industrial Oil and Fat Products

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The brain contains high concentrations of lipids, and lipid homoeostasis is fundamental to the maintenance of brain health. Alterations of the main lipid classes have been shown to be involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Dietary omega‐3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), can have favorable effects on brain structure and cognitive functions and might be a useful strategy in the prevention of AD. However, further randomized controlled trials are required before omega‐3 PUFAs can be recommended as a preventive measure for mild cognitive impairment and dementia. Omega‐3 PUFAs may also have therapeutic potential in Parkinson's and Huntington's diseases. PUFAs can exert anti‐inflammatory effects that may be relevant to multiple sclerosis (MS). However, controlled studies regarding the potential benefits of PUFA supplementation in MS have shown inconclusive results. To determine whether omega‐3 PUFAs can provide neuroprotective effects in neurodegenerative diseases, biological markers for an early identification of individuals at risk need to be found. Furthermore, the demonstration of neuroprotective efficacy in clinical studies is a significant challenge.

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Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington’s disease

Cited by 106 publications

References 27 publications

Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Lipids in the Treatment of Neurodegenerative Diseases

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