Preferential loss of striato‐external pallidal projection neurons in presymptomatic Huntington's disease

Albin, Roger L.; Reiner, Anton; Anderson, Keith D.; Dure, Leon S.; Handelin, Barbara; Balfour, Rosemary; Whetsell, William O.; Penney, John B.; Young, Anne B.

doi:10.1002/ana.410310412

Cited by 337 publications

(219 citation statements)

References 19 publications

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“…The projection neurons are themselves divided into two classes. Both types contain GABA as a primary neurotransmitter, but of the two populations of striatal projection neurons, those of the indirect pathway (i.e., enkephalin/GABA-containing neurons) are affected first, thus providing an anatomical substrate for the increased movement that is the hallmark of HD (Reiner et al, 1988;Albin et al, 1992). In later stages of adult HD, both populations of striatal projection neurons are affected, with concomitant loss of markers of the direct pathway (i.e.…”

Section: Discussionmentioning

confidence: 99%

Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease

Masuda

et al. 2008

Neurobiology of Disease

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, incoordination, and shortened life-span, and by huntingtin inclusions and neurodegeneration. We previously screened the 1040 FDA-approved compounds from the NINDS compound library and found that a compound, nipecotic-acid, significantly reduced mutant huntingtin aggregations and blocked cell toxicity in an inducible cell model of HD. Because nipecotic-acid does not cross the blood-brain barrier (BBB), we studied its analogue, tiagabine, which is able to cross the BBB, in both N171-82Q and R6/2 transgenic mouse models of HD. Tiagabine was administered intraperitoneally at 2 and 5 mg/kg daily in HD mice. We found that tiagabine extended survival, improved motor performance, and attenuated brain atrophy and neurodegeneration in N171-82Q HD mice. These beneficial effects were further confirmed in R6/2 HD mice. The levels of tiagabine at effective doses in mouse serum are comparable to the levels in human patients treated with tiagabine. These results suggest that tiagabine may have beneficial effects in the treatment of HD. Because tiagabine is an FDA-approved drug, it may be a promising candidate for future clinical trials for the treatment of HD.

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Section: Discussionmentioning

confidence: 99%

Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease

Masuda

et al. 2008

Neurobiology of Disease

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“…AAV-GDNF improved rotorod performance, delayed and attenuated clasping behavior, and preserved the number and size of striatal neurons in this model. Both clinical (34)(35)(36) and preclinical (3,31,33) studies suggest that HD symptoms can occur before the frank loss of striatal neurons. The prevention of neuronal atrophy by AAV-GDNF suggests that an early aspect of the degenerative process that mediates symptom onset might be prevented by this treatment.…”

Section: Discussionmentioning

confidence: 99%

Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington’s disease

McBride

Ramaswamy

Gasmi³

et al. 2006

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

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Huntington's disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin. These excessive repeats confer a toxic gain of function on huntingtin, which leads to the degeneration of striatal and cortical neurons and a devastating motor, cognitive, and psychological disorder. Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD. We previously demonstrated that viral delivery of glial cell line-derived neurotrophic factor (GDNF) provides structural and functional neuroprotection in a rat neurotoxin model of HD. In this report we demonstrate that viral delivery of GDNF into the striatum of presymptomatic mice ameliorates behavioral deficits on the accelerating rotorod and hind limb clasping tests in transgenic HD mice. Behavioral neuroprotection was associated with anatomical preservation of the number and size of striatal neurons from cell death and cell atrophy. Additionally, GDNF-treated mice had a lower percentage of neurons containing mutant huntingtin-stained inclusion bodies, a hallmark of HD pathology. These data further support the concept that viral vector delivery of GDNF may be a viable treatment for patients suffering from HD.gene therapy ͉ neurodegeneration ͉ neuroprotection ͉ polyglutamine ͉ adenoassociated virus H untington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from an expanded trinucleotide (CAG: cytosine, adenine, and guanine) repeat at the IT15 locus on chromosome 4 (1) within the huntingtin gene. The abnormal DNA is translated into mutant huntingtin with an expanded glutamine stretch at the N terminus of the protein. The excessive number of glutamine repeats is responsible for the misfolding of huntingtin and the subsequent formation of neuronal inclusions, degeneration of striatal and cortical neurons, and a triad of symptoms including severe motor, cognitive, and psychological disturbances that are ultimately fatal.To date, HD remains incurable. Several therapies have yielded positive results in animal models, including those that alleviate potential glutamate-induced excitotoxicity such as riluzole and remacemide (2-4); those that increase the production of energy in the form of ATP in the cell, including creatine and coenzyme Q 10 (5-9); those that inhibit caspase activation and apoptosis, such as minocycline (10, 11); and those that aim at replacing degenerating cells by means of fetal tissue transplantation (12-18). However, when tested clinically, none has made a major impact in the symptomatic treatment of HD, nor have any demonstrated the ability to alter the natural history of the disease by preventing cell death.Genetic testing can identify mutated gene carriers destined to suffer from HD. Unlike other neurodegenerative disorders, identification of the genetic marker provides the unique opportunity to intercede therapeutically before the onset of symptoms that result from n...

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“…Polyglutamine expansion leads to a conformational change in the huntingtin protein, causing the formation of large aggregations in the nucleus and cytoplasm. These htt and mutant htt (mhtt) genes are expressed ubiquitously in human tissues, spiny neurons of the putamen and caudate nucleus in HD (Arrasate et al 2004;Albin et al 1992). The recent evidence suggested that the involvement of ROS in HD pathogenesis is by dysfunctioning of the mitochondrial complex II (Calkins et al 2005).…”

Section: Huntington's Diseasementioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

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The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

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Preferential loss of striato‐external pallidal projection neurons in presymptomatic Huntington's disease

Cited by 337 publications

References 19 publications

Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease

Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease

Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington’s disease

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

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