Aleksandar Arsović, Melanie Vanessa Halbach, Júlia Canet-Pons, Dilhan Esen-Sehir, Claudia Döring, Florian Freudenberg, Nicoletta Czechowska, Kay Seidel, Stephan L Baader, Suzana Gispert, Nesli-Ece Sen, Georg Auburger
Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine expansion in Ataxin-2 (ATXN2). This factor binds RNA/proteins to modify metabolism after stress, and to control calcium (Ca2+ ) homeostasis after stimuli. Cerebellar ataxias and corticospinal motor neuron degeneration are determined by gain/loss in ATXN2 function, so we aimed to identify key molecules in this atrophic process, as potential disease progression markers. Our Atxn2 -CAG100-Knock-In mouse faithfully models features observed in patients at pre-onset, early and terminal stages...
September 12, 2020: International Journal of Molecular Sciences
Emery Haley, Wooyoung Choi, Chen Fan, Weinan Sun, Juan Du, Wei Lü
Transient receptor potential channels (TRPCs) of the canonical TRP subfamily are nonselective cation channels that play an essential role in calcium homeostasis, particularly store-operated calcium entry, which is critical to maintaining proper function of synaptic vesicle release and intracellular signaling pathways. Accordingly, TRPC channels have been implicated in a variety of human diseases including cardiovascular disorders such as cardiac hypertrophy, neurodegenerative disorders such as Parkinson's disease, and neurologic disorders such as spinocerebellar ataxia...
January 7, 2019: Journal of Visualized Experiments: JoVE
Caleigh M Azumaya, Francisco Sierra-Valdez, Julio F Cordero-Morales, Terunaga Nakagawa
The kidney maintains the internal milieu by regulating the retention and excretion of proteins, ions, and small molecules. The glomerular podocyte forms the slit diaphragm of the ultrafiltration filter, whose damage leads to progressive kidney failure and focal segmental glomerulosclerosis (FSGS). The canonical transient receptor potential 6 (TRPC6) ion channel is expressed in the podocyte, and mutations in its cytoplasmic domain cause FSGS in humans. In vitro evaluation of disease-causing mutations in TRPC6 has revealed that these genetic alterations result in abnormal ion channel gating...
June 29, 2018: Journal of Biological Chemistry
Chen Fan, Wooyoung Choi, Weinan Sun, Juan Du, Wei Lu
The TRPC channels are crucially involved in store-operated calcium entry and calcium homeostasis, and they are implicated in human diseases such as neurodegenerative disease, cardiac hypertrophy, and spinocerebellar ataxia. We present a structure of the full-length human TRPC3, a lipid-gated TRPC member, in a lipid-occupied, closed state at 3.3 Angstrom. TRPC3 has four elbow-like membrane reentrant helices prior to the first transmembrane helix. The TRP helix is perpendicular to, and thus disengaged from, the pore-lining S6, suggesting a different gating mechanism from other TRP subfamily channels...
May 4, 2018: ELife
Sonya M Hanson, Mark S P Sansom, Esther B E Becker
A gain-of-function mutation (T635A) in the transient receptor potential (TRP) channel TRPC3 results in abnormal channel gating and causes cerebellar ataxia in the dominant Moonwalker (Mwk) mouse mutant. However, the underlying molecular and structural mechanisms are unclear. Here, we used a combined approach of computational modeling and functional characterization of proposed TRPC3 mutants. Our findings support a mechanism by which the hydrogen bonding capability of threonine 635 plays a significant role in maintaining a stable, closed state channel...
July 7, 2015: Biochemistry
Jana Hartmann, Arthur Konnerth
The transient receptor potential (TRPC) proteins form non-selective cation channels that are activated downstream of Gq-phospholipase C-coupled receptors. TRPC3, one of the seven members of the TRPC subfamily, combines functions of an unspecific ion channel and a signal transducer. In the mammalian brain, the expression of TRPC3 is highest in cerebellar Purkinje cells, the principal neurons, and the sole output of the cerebellar cortex. In this review, we summarize findings identifying TRPC3 channels as integral components of glutamatergic metabotropic synaptic transmission...
September 2015: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Anna Dulneva, Sheena Lee, Peter L Oliver, Katalin Di Gleria, Benedikt M Kessler, Kay E Davies, Esther B E Becker
The Moonwalker (Mwk) mouse is a model of dominantly inherited cerebellar ataxia caused by a gain-of-function mutation in the transient receptor potential (TRP) channel TRPC3. Here, we report impairments in dendritic growth and synapse formation early on during Purkinje cell development in the Mwk cerebellum that are accompanied by alterations in calcium signaling. To elucidate the molecular effector pathways that regulate Purkinje cell dendritic arborization downstream of mutant TRPC3, we employed transcriptomic analysis of developing Purkinje cells isolated by laser-capture microdissection...
July 15, 2015: Human Molecular Genetics
Esther B E Becker
The dominantly inherited cerebellar ataxias are a clinically and genetically heterogeneous group of neurodegenerative disorders. Studies using mouse models as well as recent genetic and transcriptomic human findings point to an important role for TRPC3 signaling in cerebellar ataxia.
December 2017: Cerebellum
Esther B E Becker
The Moonwalker (Mwk) mouse is a recent model of dominantly inherited cerebellar ataxia. The motor phenotype of the Mwk mouse is due to a gain-of-function mutation in the gene encoding the cation-permeable transient receptor potential channel (TRPC3). This mutation converts a threonine into an alanine in the highly conserved cytoplasmic S4-S5 linker of the channel, affecting channel gating. TRPC3 is highly expressed in cerebellar Purkinje cells and type II unipolar brush cells that both degenerate in the Mwk mouse...
October 2014: Cerebellum
Gabriella Sekerková, Jin-Ah Kim, Maximiliano J Nigro, Esther B E Becker, Jana Hartmann, Lutz Birnbaumer, Enrico Mugnaini, Marco Martina
Transient receptor potential "canonical" cation channels (TRPC) are involved in many cellular activities, including neuronal synaptic transmission. These channels couple lipid metabolism, calcium homeostasis, and electrophysiological properties as they are calcium permeable and activated through the phospholipase C pathway and by diacylglycerol. The TRPC3 subunit is abundantly expressed in Purkinje cells (PCs), where it mediates slow metabotropic glutamate receptor-mediated synaptic responses. Recently, it has been shown that heterozygous moonwalker mice, which are a model of cerebellar ataxia, carry a dominant gain-of-function mutation (T635A) in the TRPC3 gene...
December 11, 2013: Journal of Neuroscience
Anton N Shuvaev, Hajime Horiuchi, Takahiro Seki, Hanna Goenawan, Tomohiko Irie, Akira Iizuka, Norio Sakai, Hirokazu Hirai
Cerebellar Purkinje cells (PCs) express a large amount of the γ isoform of protein kinase C (PKCγ) and a modest level of PKCα. The PKCγ is involved in the pruning of climbing fiber (CF) synapses from developing PCs, and PKCα plays a critical role in long-term depression (LTD) at parallel fiber (PF)-PC synapses. Moreover, the PKC signaling in PCs negatively modulates the nonselective transient receptor potential cation channel type 3 (TRPC3), the opening of which elicits slow EPSCs at PF-PC synapses. Autosomal dominant spinocerebellar ataxia type 14 (SCA14) is caused by mutations in PKCγ...
October 5, 2011: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Alex Martin-Trujillo, Isabel Iglesias-Platas, Eliecer Coto, Marc Corral-Juan, Hector San Nicolás, Jordi Corral, Victor Volpini, Antoni Matilla-Dueñas, David Monk
A fundamental challenge in the post-genomics era is to understand how genetic variants can influence phenotypic variability and disease. Recent observations from a number of studies have highlighted a mechanism by which common genetic polymorphisms can influence DNA methylation, a major epigenetic silencing mechanism. We report that the alternative promoter of the human TRPC3 gene is regulated by allelic DNA methylation, dictated by the genotype of a single base pair polymorphism, rs13121031 located within the promoter CpG island...
October 1, 2011: Epigenetics: Official Journal of the DNA Methylation Society
Kazuhiro Mitsumura, Nobutake Hosoi, Nobuhiko Furuya, Hirokazu Hirai
Staggerer mutant mice have functional loss of a transcription factor, retinoid-related orphan receptor α (RORα), which is abundantly expressed in Purkinje cells (PCs) of the cerebellum.Homozygous staggerer (sg/sg)mice show cerebellar hypoplasia and congenital ataxia. Sg/sg mice serve as an important extreme mouse model of the hereditary spinocerebellar ataxia type 1 (SCA1), since it has been shown that RORα dysfunction is strongly correlated with SCA1 pathogenesis. However, synaptic abnormalities, especially at parallel fibre (PF)-PC synapses, in SCA1-related sg/sg mice have not been examined in detail electrophysiologically...
July 1, 2011: Journal of Physiology
Esther B E Becker, Brent L Fogel, Sanjeev Rajakulendran, Anna Dulneva, Michael G Hanna, Susan L Perlman, Daniel H Geschwind, Kay E Davies
The hereditary cerebellar ataxias are a diverse group of neurodegenerative disorders primarily characterised by loss of balance and coordination due to dysfunction of the cerebellum and its associated pathways. Although many genetic mutations causing inherited cerebellar ataxia have been identified, a significant percentage of patients remain whose cause is unknown. The transient receptor potential (TRP) family member TRPC3 is a non-selective cation channel linked to key signalling pathways that are affected in cerebellar ataxia...
June 2011: Cerebellum
Esther B E Becker, Peter L Oliver, Maike D Glitsch, Gareth T Banks, Francesca Achilli, Andrea Hardy, Patrick M Nolan, Elizabeth M C Fisher, Kay E Davies
The hereditary ataxias are a complex group of neurological disorders characterized by the degeneration of the cerebellum and its associated connections. The molecular mechanisms that trigger the loss of Purkinje cells in this group of diseases remain incompletely understood. Here, we report a previously undescribed dominant mouse model of cerebellar ataxia, moonwalker (Mwk), that displays motor and coordination defects and loss of cerebellar Purkinje cells. Mwk mice harbor a gain-of-function mutation (T635A) in the Trpc3 gene encoding the nonselective transient receptor potential cation channel, type C3 (TRPC3), resulting in altered TRPC3 channel gating...
April 21, 2009: Proceedings of the National Academy of Sciences of the United States of America
Naoko Adachi, Takeshi Kobayashi, Hideyuki Takahashi, Takumi Kawasaki, Yasuhito Shirai, Takehiko Ueyama, Toshio Matsuda, Takahiro Seki, Norio Sakai, Naoaki Saito
Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disease caused by mutations in protein kinase Cgamma (PKCgamma). Interestingly, 18 of 22 mutations are concentrated in the C1 domain, which binds diacylglycerol and is necessary for translocation and regulation of PKCgamma kinase activity. To determine the effect of these mutations on PKCgamma function and the pathology of SCA14, we investigated the enzymological properties of the mutant PKCgammas. We found that wild-type PKCgamma, but not C1 domain mutants, inhibits Ca2+ influx in response to muscarinic receptor stimulation...
July 11, 2008: Journal of Biological Chemistry
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