Corticostriatal circuit dysfunction in Huntington‘s disease: intersection of glutamate, dopamine and calcium

Miller, Benjamin R.; Bezprozvanny, Ilya

doi:10.2217/fnl.10.41

Cited by 55 publications

(48 citation statements)

References 209 publications

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“…Early neuropathological features of HD include perturbed corticostriatal synaptic function and connectivity (Miller and Bezprozvanny, 2010; Milnerwood and Raymond, 2007; Milnerwood and Raymond, 2010; Murmu et al, 2013; Orth et al, 2010; Schippling et al, 2009), eventually leading to overt neurodegeneration of medium spiny neurons (MSNs) in the striatum (Myers et al, 1988; Vonsattel and DiFiglia, 1998). Perturbed stability of synaptic spines has been suggested to underlie the development of HD symptoms (Bezprozvanny and Hiesinger, 2013; Murmu et al, 2013; Ryskamp et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Ryskamp

Geva

et al. 2017

Neurobiology of Disease

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103

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The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated “dopamine stabilizer”, has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for pridopidine, we evaluated the relevance of S1R as a therapeutic target of pridopidine in HD. S1R is an endoplasmic reticulum - (ER) resident transmembrane protein and is regulated by ER calcium homeostasis, which is perturbed in HD. Consistent with ER calcium dysregulation, we observed striatal upregulation of S1R in aged YAC128 transgenic HD mice and HD patients. We previously demonstrated that dendritic MSN spines are lost in aged corticostriatal co-cultures from YAC128 mice. We report here that pridopidine and the chemically similar S1R agonist 3-PPP prevent MSN spine loss in aging YAC128 co-cultures. Spine protection was blocked by neuronal deletion of S1R. Pridopidine treatment suppressed supranormal ER Ca2+ release, restored ER calcium levels and reduced excessive store-operated calcium (SOC) entry in spines, which may account for its synaptoprotective effects. Normalization of ER Ca2+ levels by pridopidine was prevented by S1R deletion. To evaluate long-term effects of pridopidine, we analyzed expression profiles of calcium signaling genes. Pridopidine elevated striatal expression of calbindin and homer1a, whereas their striatal expression was reduced in aged Q175KI and YAC128 HD mouse models compared to WT. Pridopidine and 3-PPP are proposed to prevent calcium dysregulation and synaptic loss in a YAC128 corticostriatal co-culture model of HD. The actions of pridopidine were mediated by S1R and led to normalization of ER Ca2+ release, ER Ca2+ levels and spine SOC entry in YAC128 MSNs. This is a new potential mechanism of action for pridopidine, highlighting S1R as a potential target for HD therapy. Upregulation of striatal proteins that regulate calcium, including calbindin and homer1a, upon chronic therapy with pridopidine, may further contribute to long-term beneficial effects of pridopidine in HD.

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Section: Introductionmentioning

confidence: 99%

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Ryskamp

Geva

et al. 2017

Neurobiology of Disease

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103

149

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“…A number of studies indicate mitochondrial dysfunction as an important contributor to the pathology [8–14]. In addition several results point to altered Ca 2+ homeostasis and excitotoxicity in affected neurons [15, 16]. …”

Section: Introductionmentioning

confidence: 99%

Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington’s Disease

et al. 2016

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Huntington´s disease (HD) is a hereditary neurodegenerative disease resulting from an expanded polyglutamine sequence (poly-Q) in the protein huntingtin (HTT). Various studies report atrophy and metabolic pathology of skeletal muscle in HD and suggest as part of the process a fast-to-slow fiber type transition that may be caused by the pathological changes in central motor control or/and by mutant HTT in the muscle tissue itself. To investigate muscle pathology in HD, we used R6/2 mice, a common animal model for a rapidly progressing variant of the disease expressing exon 1 of the mutant human gene. We investigated alterations in the extensor digitorum longus (EDL), a typical fast-twitch muscle, and the soleus (SOL), a slow-twitch muscle. We focussed on mechanographic measurements of excised muscles using single and repetitive electrical stimulation and on the expression of the various myosin isoforms (heavy and light chains) using dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole muscle and single fiber preparations. In EDL of R6/2, the functional tests showed a left shift of the force-frequency relation and decrease in specific force. Moreover, the estimated relative contribution of the fastest myosin isoform MyHC IIb decreased, whereas the contribution of the slower MyHC IIx isoform increased. An additional change occurred in the alkali MyLC forms showing a decrease in 3f and an increase in 1f level. In SOL, a shift from fast MyHC IIa to the slow isoform I was detectable in male R6/2 mice only, and there was no evidence of isoform interconversion in the MyLC pattern. These alterations point to a partial remodeling of the contractile apparatus of R6/2 mice towards a slower contractile phenotype, predominantly in fast glycolytic fibers.

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“…For example, there is extensive evidence for dysregulated cortico-striatal synapses at early stages of Huntington’s disease (HD). It appears that synaptic changes in HD result mainly from changes in cell biological and Ca 2+ signaling mechanisms induced by mutant Huntingtin protein [178-181]. It is however possible that age-related synaptic maintenance defects outlined in this review contribute to the vulnerability of synapses to other toxic insults, such as mutant Huntingtin-polyQ protein.…”

Section: Introductionmentioning

confidence: 99%

The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration

Bezprozvanny

Hiesinger

2013

Mol Neurodegeneration

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Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional. This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normal synapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseasesis largely unclear. In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca2+) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration.

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Corticostriatal circuit dysfunction in Huntington‘s disease: intersection of glutamate, dopamine and calcium

Cited by 55 publications

References 209 publications

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington’s Disease

The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration

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