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Synaptic protein dysregulation in myotonic dystrophy type 1: Disease neuropathogenesis beyond missplicing.

Hernández-Hernández O, Sicot G, Dinca DM, Huguet A, Nicole A, Buée L, Munnich A, Sergeant N, Gourdon G, Gomes-Pereira M - Rare Dis (2013)

Bottom Line: We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains.In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes.Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program.

View Article: PubMed Central - PubMed

Affiliation: Inserm U781; Hôpital Necker Enfants Malades; Paris, France ; Laboratorio de Medicina Genómica; Departamento de Genética; Instituto Nacional de Rehabilitación; Calzada México Xochimilco, México.

ABSTRACT
The toxicity of expanded transcripts in myotonic dystrophy type 1 (DM1) is mainly mediated by the disruption of alternative splicing. However, the detailed disease mechanisms in the central nervous system (CNS) have not been fully elucidated. In our recent study, we demonstrated that the accumulation of mutant transcripts in the CNS of a mouse model of DM1 disturbs splicing in a region-specific manner. We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains. In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes. Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program.

No MeSH data available.


Related in: MedlinePlus

Figure 3. Schematic representation of the role of RAB3A and SYN1 in the dynamics of synaptic vesicles. (A) RAB3A is an abundant vesicle-associated protein that regulates synaptic efficiency. The reported functions of RAB3A in exocytosis range from docking and fusion of the synaptic vesicle to its subsequent recycling. RAB3A functions through a variety of interactions with multiple effector proteins. The upregulation of RAB3A likely perturbs the highly regulated vesicle dynamics and release, affecting neurotransmission and synaptic function in DM1. (B) SYN1 is expressed in mature neurons, where it associates with the cytoplasmic surface of synaptic vesicles. SYN1 regulates the supply of synaptic vesicles available for exocytosis by binding to both vesicles and actin cytoskeleton in a phosphorylation-dependent manner. Under resting conditions, non-phosphorylated SYN1 attaches synaptic vesicles to the actin cytoskeleton. Synaptic stimulation induces SYN1 phosphorylation that facilitates vesicle dissociation from cytoskeleton and potentiates exocytosis. Abnormal SYN1 hyperphosphorylation in DM1 likely dysregulates neuronal exocytosis and vesicle release.
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Figure 3: Figure 3. Schematic representation of the role of RAB3A and SYN1 in the dynamics of synaptic vesicles. (A) RAB3A is an abundant vesicle-associated protein that regulates synaptic efficiency. The reported functions of RAB3A in exocytosis range from docking and fusion of the synaptic vesicle to its subsequent recycling. RAB3A functions through a variety of interactions with multiple effector proteins. The upregulation of RAB3A likely perturbs the highly regulated vesicle dynamics and release, affecting neurotransmission and synaptic function in DM1. (B) SYN1 is expressed in mature neurons, where it associates with the cytoplasmic surface of synaptic vesicles. SYN1 regulates the supply of synaptic vesicles available for exocytosis by binding to both vesicles and actin cytoskeleton in a phosphorylation-dependent manner. Under resting conditions, non-phosphorylated SYN1 attaches synaptic vesicles to the actin cytoskeleton. Synaptic stimulation induces SYN1 phosphorylation that facilitates vesicle dissociation from cytoskeleton and potentiates exocytosis. Abnormal SYN1 hyperphosphorylation in DM1 likely dysregulates neuronal exocytosis and vesicle release.

Mentions: DMSXL mice recreate relevant signs of RNA toxicity in the CNS, associated with behavioral, electrophysiological and neurochemical changes. In the search for the mechanisms and dysfunctional pathways behind these phenotypes, we found altered expression and phosphorylation of synaptic proteins, which are independent of splicing dysregulation. RAB3A is an abundant synaptic vesicle protein that regulates neurotransmission, through the interaction with other synaptic proteins that control vesicle fusion to the cell membrane.30 SYN1 regulates neuronal vesicle release in a phosphorylation-dependent manner31 (Fig. 3). As a result, RAB3A upregulation and SYN1 hyperphosphorylation disrupts synaptic function and neurotransmitter release, likely contributing to the cognitive and behavioral deficits of DMSXL mice and the neuropsychological manifestations of DM1 patients.


Synaptic protein dysregulation in myotonic dystrophy type 1: Disease neuropathogenesis beyond missplicing.

Hernández-Hernández O, Sicot G, Dinca DM, Huguet A, Nicole A, Buée L, Munnich A, Sergeant N, Gourdon G, Gomes-Pereira M - Rare Dis (2013)

Figure 3. Schematic representation of the role of RAB3A and SYN1 in the dynamics of synaptic vesicles. (A) RAB3A is an abundant vesicle-associated protein that regulates synaptic efficiency. The reported functions of RAB3A in exocytosis range from docking and fusion of the synaptic vesicle to its subsequent recycling. RAB3A functions through a variety of interactions with multiple effector proteins. The upregulation of RAB3A likely perturbs the highly regulated vesicle dynamics and release, affecting neurotransmission and synaptic function in DM1. (B) SYN1 is expressed in mature neurons, where it associates with the cytoplasmic surface of synaptic vesicles. SYN1 regulates the supply of synaptic vesicles available for exocytosis by binding to both vesicles and actin cytoskeleton in a phosphorylation-dependent manner. Under resting conditions, non-phosphorylated SYN1 attaches synaptic vesicles to the actin cytoskeleton. Synaptic stimulation induces SYN1 phosphorylation that facilitates vesicle dissociation from cytoskeleton and potentiates exocytosis. Abnormal SYN1 hyperphosphorylation in DM1 likely dysregulates neuronal exocytosis and vesicle release.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927487&req=5

Figure 3: Figure 3. Schematic representation of the role of RAB3A and SYN1 in the dynamics of synaptic vesicles. (A) RAB3A is an abundant vesicle-associated protein that regulates synaptic efficiency. The reported functions of RAB3A in exocytosis range from docking and fusion of the synaptic vesicle to its subsequent recycling. RAB3A functions through a variety of interactions with multiple effector proteins. The upregulation of RAB3A likely perturbs the highly regulated vesicle dynamics and release, affecting neurotransmission and synaptic function in DM1. (B) SYN1 is expressed in mature neurons, where it associates with the cytoplasmic surface of synaptic vesicles. SYN1 regulates the supply of synaptic vesicles available for exocytosis by binding to both vesicles and actin cytoskeleton in a phosphorylation-dependent manner. Under resting conditions, non-phosphorylated SYN1 attaches synaptic vesicles to the actin cytoskeleton. Synaptic stimulation induces SYN1 phosphorylation that facilitates vesicle dissociation from cytoskeleton and potentiates exocytosis. Abnormal SYN1 hyperphosphorylation in DM1 likely dysregulates neuronal exocytosis and vesicle release.
Mentions: DMSXL mice recreate relevant signs of RNA toxicity in the CNS, associated with behavioral, electrophysiological and neurochemical changes. In the search for the mechanisms and dysfunctional pathways behind these phenotypes, we found altered expression and phosphorylation of synaptic proteins, which are independent of splicing dysregulation. RAB3A is an abundant synaptic vesicle protein that regulates neurotransmission, through the interaction with other synaptic proteins that control vesicle fusion to the cell membrane.30 SYN1 regulates neuronal vesicle release in a phosphorylation-dependent manner31 (Fig. 3). As a result, RAB3A upregulation and SYN1 hyperphosphorylation disrupts synaptic function and neurotransmitter release, likely contributing to the cognitive and behavioral deficits of DMSXL mice and the neuropsychological manifestations of DM1 patients.

Bottom Line: We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains.In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes.Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program.

View Article: PubMed Central - PubMed

Affiliation: Inserm U781; Hôpital Necker Enfants Malades; Paris, France ; Laboratorio de Medicina Genómica; Departamento de Genética; Instituto Nacional de Rehabilitación; Calzada México Xochimilco, México.

ABSTRACT
The toxicity of expanded transcripts in myotonic dystrophy type 1 (DM1) is mainly mediated by the disruption of alternative splicing. However, the detailed disease mechanisms in the central nervous system (CNS) have not been fully elucidated. In our recent study, we demonstrated that the accumulation of mutant transcripts in the CNS of a mouse model of DM1 disturbs splicing in a region-specific manner. We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains. In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes. Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program.

No MeSH data available.


Related in: MedlinePlus