scholarly journals Kv3.3 channels harbouring a mutation of spinocerebellar ataxia type 13 alter excitability and induce cell death in cultured cerebellar Purkinje cells

2013 ◽  
Vol 592 (1) ◽  
pp. 229-247 ◽  
Author(s):  
Tomohiko Irie ◽  
Yasunori Matsuzaki ◽  
Yuko Sekino ◽  
Hirokazu Hirai
Keyword(s):  
Cell Death ◽  
Purkinje Cells ◽  
Spinocerebellar Ataxia ◽  
Spinocerebellar Ataxia Type ◽  
Induce Cell Death ◽  
Cerebellar Purkinje Cells

scholarly journals Cerebellar neuronal dysfunction accompanies early motor symptoms in Spinocerebellar Ataxia Type 3 and is partially alleviated upon chronic citalopram treatment

2021 ◽  
Author(s):  
KJ Palarz ◽  
A Neves-Carvalho ◽  
S Duarte-Silva ◽  
P Maciel ◽  
K Khodakhah
Keyword(s):  
Mouse Model ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Spinocerebellar Ataxia ◽  
Cell Activity ◽  
Spinocerebellar Ataxia Type ◽  
Neuronal Dysfunction ◽  
Spinocerebellar Ataxia Type 3 ◽  
Cell Dysfunction ◽  
Type 3

ABSTRACTSpinocerebellar ataxia type 3 (SCA3) is an adult-onset, progressive ataxia with no current disease modifying treatments. SCA3 patients have mild degeneration of the cerebellum, a brain area involved in motor coordination and maintenance of balance, as well as of the brainstem, of the spinal cord and of other movement-related subcortical areas. However, both SCA3 patients and SCA3 mouse models present clinical symptoms before any gross pathology is detectable, which suggests neuronal dysfunction precedes neurodegeneration, and opens an opportunity for therapeutic intervention. Such observations also raise the question of what triggers these abnormal motor phenotypes. Purkinje cells are the major computational unit within the cerebellum and are responsible for facilitating coordinated movements. Abnormal Purkinje cell activity is sufficient to cause ataxia. In this study, we show that the CMVMJD135 mouse model of SCA3 has dysfunctional deep cerebellar nuclei and Purkinje cells. Both cell types have increased irregularity as measured by inter-spike interval coefficient of variation. Purkinje cell dysfunction is likely a combination of intrinsic and extrinsic (synaptic) dysfunction. Interestingly, Citalopram, a selective serotonin reuptake inhibitor previously shown to alleviate disease in CMVMJD135 mice, also improved cerebellar neuron function in the CMVMJD135 mouse model. Specifically, we found that Purkinje cell dysfunction when synaptic transmission is intact was alleviated with citalopram treatment, however, intrinsic Purkinje cell dysfunction was not alleviated. Altogether, our findings suggest that cerebellar neuronal dysfunction contributes to the onset of SCA3 motor dysfunction and that citalopram, while effective at alleviating the motor phenotype, does not restore Purkinje cell intrinsic activity in SCA3. A novel therapeutic approach that combines citalopram with another therapeutic that targets this intrinsic dysfunction in a complementary manner might further reduce disease burden in SCA3.

scholarly journals Modulation of Increased mGluR1 Signaling by RGS8 Protects Purkinje Cells From Dendritic Reduction and Could Be a Common Mechanism in Diverse Forms of Spinocerebellar Ataxia

2021 ◽  
Vol 8 ◽  
Author(s):  
Qin-Wei Wu ◽  
Josef P. Kapfhammer
Keyword(s):  
Purkinje Cells ◽  
Spinocerebellar Ataxia ◽  
Common Mechanism ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Spinocerebellar Ataxias ◽  
Negative Effects ◽  
The Moment ◽  
Cerebellar Purkinje Cells

Spinocerebellar ataxias (SCAs) are a group of hereditary neurodegenerative diseases which are caused by diverse genetic mutations in a variety of different genes. We have identified RGS8, a regulator of G-protein signaling, as one of the genes which are dysregulated in different mouse models of SCA (e.g., SCA1, SCA2, SCA7, and SCA14). In the moment, little is known about the role of RGS8 for pathogenesis of spinocerebellar ataxia. We have studied the expression of RGS8 in the cerebellum in more detail and show that it is specifically expressed in mouse cerebellar Purkinje cells. In a mouse model of SCA14 with increased PKCγ activity, RGS8 expression was also increased. RGS8 overexpression could partially counteract the negative effects of DHPG-induced mGluR1 signaling for the expansion of Purkinje cell dendrites. Our results suggest that the increased expression of RGS8 is an important mediator of mGluR1 pathway dysregulation in Purkinje cells. These findings provide new insights in the role of RGS8 and mGluR1 signaling in Purkinje cells and for the pathology of SCAs.

scholarly journals PKCγ-Mediated Phosphorylation of CRMP2 Regulates Dendritic Outgrowth in Cerebellar Purkinje Cells

2020 ◽  
Vol 57 (12) ◽  
pp. 5150-5166
Author(s):  
Sabine C. Winkler ◽  
Etsuko Shimobayashi ◽  
Josef P. Kapfhammer
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Synaptic Function ◽  
Mass Spectrometry Analysis ◽  
Spinocerebellar Ataxia Type ◽  
Proximity Ligation Assay ◽  
Wild Type ◽  
Dynamic Regulation ◽  
Dendritic Development ◽  
Cerebellar Purkinje Cells

Abstract The signalling protein PKCγ is a major regulator of Purkinje cell development and synaptic function. We have shown previously that increased PKCγ activity impairs dendritic development of cerebellar Purkinje cells. Mutations in the protein kinase Cγ gene (PRKCG) cause spinocerebellar ataxia type 14 (SCA14). In a transgenic mouse model of SCA14 expressing the human S361G mutation, Purkinje cell dendritic development is impaired in cerebellar slice cultures similar to pharmacological activation of PKC. The mechanisms of PKCγ-driven inhibition of dendritic growth are still unclear. Using immunoprecipitation-coupled mass spectrometry analysis, we have identified collapsin response mediator protein 2 (CRMP2) as a protein interacting with constitutive active PKCγ(S361G) and confirmed the interaction with the Duolink™ proximity ligation assay. We show that in cerebellar slice cultures from PKCγ(S361G)-mice, phosphorylation of CRMP2 at the known PKC target site Thr555 is increased in Purkinje cells confirming phosphorylation of CRMP2 by PKCγ. miRNA-mediated CRMP2 knockdown decreased Purkinje cell dendritic outgrowth in dissociated cerebellar cultures as did the transfection of CRMP2 mutants with a modified Thr555 site. In contrast, dendritic development was normal after wild-type CRMP2 overexpression. In a novel knock-in mouse expressing only the phospho-defective T555A-mutant CRMP2, Purkinje cell dendritic development was reduced in dissociated cultures. This reduction could be rescued by transfecting wild-type CRMP2 but only partially by the phospho-mimetic T555D-mutant. Our findings establish CRMP2 as an important target of PKCγ phosphorylation in Purkinje cells mediating its control of dendritic development. Dynamic regulation of CRMP2 phosphorylation via PKCγ is required for its correct function.

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