Abnormal Phosphorylation of Synapsin I Predicts a Neuronal Transmission Impairment in the R6/2 Huntington's Disease Transgenic Mice

Liévens, Jean-Charles; Woodman, Benjamin; Mahal, Amarbirpal; Bates, Gillian P.

doi:10.1006/mcne.2002.1152

Cited by 68 publications

(48 citation statements)

References 60 publications

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“…Lievens and co-workers showed that phosphorylation at sites 3-5 in synapsin I is changed in the R6/2-mouse model of HD. They also reported an increase in ERK phosphorylation in the striatum of old R6/2 mice and a decrease in the levels of calcineurin-B [59]. Phosphorylation of synapsin I at sites 3-5 leads to a reduced affinity to actin filaments [59] and thereby to a possible decrease of the reserve pool of vesicles.…”

Section: Mutant Huntingtin Affects the Exocytotic Processmentioning

confidence: 94%

“…Third, mutant huntingtin can change post-translational modifications of the proteins once they are formed, e.g. by affecting the state of phosphorylation [59]. Finally, in some cases mutant huntingtin may affect the functions of a given protein and its normal interaction partners by changing the binding affinity without affecting their expression levels, phosphorylation states, or sequestering them in aggregates (reviewed in [20,54]).…”

Section: Alterations Of Synaptic Components In Hdmentioning

confidence: 98%

“…Phosphorylation at these sites is regulated by calcium/calmodulin-dependent protein kinase (CaMK) II, CaMKIV, extracellular-signal-related kinase (ERK)-1 and ERK2. Dephosphorylation is dependent on the action of calcineurin and protein phosphatase 2A (for details see [59]). Lievens and co-workers showed that phosphorylation at sites 3-5 in synapsin I is changed in the R6/2-mouse model of HD.…”

Section: Mutant Huntingtin Affects the Exocytotic Processmentioning

confidence: 99%

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Synaptic dysfunction in Huntington’s disease: a new perspective

Smith

Brundin

2005

Cell. Mol. Life Sci.

143

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Huntington's disease (HD) is caused by a polyglutamine expansion in the protein huntingtin and is characterized by intraneuronal inclusions and widespread neuronal death at the late stage of the disease. In research, most of the emphasis has been on understanding the cell death and its mechanisms. Until recently, it was believed that the vast majority, if not all, of the symptoms in HD are a direct consequence of neurodegeneration. However, increasing evidence shows that subtle alterations in synaptic function could underlie the early symptoms. It is of particular interest to understand the nature of this neuronal dysfunction. Normal huntingtin interacts with various cytoskeletal and synaptic vesicle proteins that are essential for exocytosis and endocytosis. Altered interactions of mutant huntingtin with its associated partners could contribute to abnormal synaptic transmission in HD. This review describes recent advances in understanding synaptic dysfunction in HD.

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Section: Mutant Huntingtin Affects the Exocytotic Processmentioning

confidence: 94%

Section: Alterations Of Synaptic Components In Hdmentioning

confidence: 98%

Section: Mutant Huntingtin Affects the Exocytotic Processmentioning

confidence: 99%

See 1 more Smart Citation

Synaptic dysfunction in Huntington’s disease: a new perspective

Smith

Brundin

2005

Cell. Mol. Life Sci.

143

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“…Proteins involved in the control of neurotransmitter release such as complexin II, synaptobrevin and synapsin I are affected early (Liévens et al, 2002;. Rabphilin 3A, another protein involved in exocytosis, is also substantially decreased in synapses of most brain regions in R6/1 mice.…”

Section: Synaptic Responsesmentioning

confidence: 99%

The corticostriatal pathway in Huntington's disease

Cepeda

André

et al. 2007

Progress in Neurobiology

283

265

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The corticostriatal pathway provides most of the excitatory glutamatergic input into the striatum and it plays an important role in the development of the phenotype of Huntington's disease (HD). This review summarizes results obtained from genetic HD mouse models concerning various alterations in this pathway. Evidence indicates that dysfunctions of striatal circuits and cortical neurons that make up the corticostriatal pathway occur during the development of the HD phenotype, well before there is significant neuronal cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium-sized spiny neurons. Some of these alterations, including increased sensitivity of N-methyl-D-aspartate receptors in subpopulations of neurons, might be constitutively present but ultimately require abnormalities in the corticostriatal inputs for the phenotype to be expressed. Dysfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. The conclusions of this review emphasize, first, the general role of neuronal circuits in the expression of the HD phenotype and, second, that both cortical and striatal circuits must be included in attempts to establish a framework for more rational therapeutic strategies in HD. Finally, as changes in cortical and striatal circuitry are complex and in some cases biphasic, therapeutic interventions should be regionally specific and take into account the temporal progression of the phenotype.

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“…Most probably there are changes at multiple levels in neurons and glia. Thus, at specific stages of the disease progression in R6/1 and R6/2 mice, there is evidence for reduced capacity to synthesize neurotransmitters such as dopamine and serotonin; 49 -51 changes in the levels of synaptic proteins; [52][53][54][55][56] alterations in a glial transport system that normally removes glutamate released from synapses. 46 Moreover, a strong body of evidence has highlighted changes in the postsynaptic elements involved in neurotransmission.…”

Section: Brain Pathology In R6 Micementioning

confidence: 99%

The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies

2005

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Summary:Huntington's disease (HD) is a genetic neurodegenerative disorder. Since identification of the disease-causing gene in 1993, a number of genetically modified animal models of HD have been generated. The first transgenic mouse models, R6/1 and R6/2 lines, were established 8 years ago. The R6/2 mice have been the best characterized and the most widely used model to study pathogenesis of HD and therapeutic interventions. In the present review, we especially focus on the characteristics of R6 transgenic mouse models and, in greater detail, describe the different therapeutic strategies that have been tested in these mice. We also, at the end, critically assess the relevance of the HD mouse models compared with the human disease and discuss how they can be best used in the future.

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Abnormal Phosphorylation of Synapsin I Predicts a Neuronal Transmission Impairment in the R6/2 Huntington's Disease Transgenic Mice

Cited by 68 publications

References 60 publications

Synaptic dysfunction in Huntington’s disease: a new perspective

Synaptic dysfunction in Huntington’s disease: a new perspective

The corticostriatal pathway in Huntington's disease

The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies

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