Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

被引:29
作者
Prestori, Francesca [1 ]
Moccia, Francesco [2 ]
D'Angelo, Egidio [1 ,3 ]
机构
[1] Univ Pavia, Dept Brain & Behav Sci, I-27100 Pavia, Italy
[2] Univ Pavia, Dept Biol & Biotechnol Lazzaro Spallanzani, I-27100 Pavia, Italy
[3] IRCCS Mondino Fdn, I-27100 Pavia, Italy
基金
欧盟地平线“2020”;
关键词
spinocerebellar ataxias; Purkinje cells; Ca2+ signaling; PROTEIN-KINASE-C; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; DOMINANT CEREBELLAR-ATAXIA; MACHADO-JOSEPH-DISEASE; LONG-TERM DEPRESSION; POLYGLUTAMINE-INDUCED NEURODEGENERATION; METABOTROPIC GLUTAMATE RECEPTORS; PURKINJE-CELL SYNAPSE; PKC-GAMMA; TRANSGENIC MICE;
D O I
10.3390/ijms21010216
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 40 autosomal-dominant genetic and neurodegenerative diseases characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly undaerstood. Emerging research suggests that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells. Ca2+ signaling in Purkinje cells is important for normal cellular function as these neurons express a variety of Ca2+ channels, Ca2+-dependent kinases and phosphatases, and Ca2+-binding proteins to tightly maintain Ca2+ homeostasis and regulate physiological Ca2+-dependent processes. Abnormal Ca2+ levels can activate toxic cascades leading to characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells via inhibitory signals; thus, Purkinje cell dysfunction or degeneration would partially or completely impair the cerebellar output in SCAs. In the absence of the inhibitory signal emanating from Purkinje cells, DCN will become more excitable, thereby affecting the motor areas receiving DCN input and resulting in uncoordinated movements. An outstanding advantage in studying the pathogenesis of SCAs is represented by the availability of a large number of animal models which mimic the phenotype observed in humans. By mainly focusing on mouse models displaying mutations or deletions in genes which encode for Ca2+ signaling-related proteins, in this review we will discuss the several pathogenic mechanisms related to deranged Ca2+ homeostasis that leads to significant Purkinje cell degeneration and dysfunction.
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页数:28
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[41]   Involvement of the cholinergic basal forebrain nuclei in spinocerebellar ataxia type 2 (SCA2) [J].
Rueb, U. ;
Farrag, K. ;
Seidel, K. ;
Brunt, E. R. ;
Heinsen, H. ;
Buerk, K. ;
Melegh, B. ;
von Gall, C. ;
Auburger, G. ;
Bohl, J. ;
Korf, H. W. ;
Hoche, F. ;
den Dunnen, W. .
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 2013, 39 (06) :634-643
[42]   Novel PRKCG/SCA14 mutation in a Dutch spinocerebellar ataxia family:: Expanding the phenotype [J].
Vlak, Monique H. M. ;
Sinke, Richard J. ;
Rabelink, Gwenda M. ;
Kremer, Berry P. H. ;
van de Warrenburg, Bart P. C. .
MOVEMENT DISORDERS, 2006, 21 (07) :1025-1028
[43]   Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significance [J].
Rüb, U ;
Brunt, ER ;
de Vos, RAI ;
Del Turco, D ;
Del Tredici, K ;
Gierga, K ;
Schultz, C ;
Ghebremedhin, E ;
Bürk, K ;
Auburger, G ;
Braak, H .
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 2004, 30 (04) :402-414
[44]   Involvement of the auditory brainstem system in spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7) [J].
Hoche, F. ;
Seidel, K. ;
Brunt, E. R. ;
Auburger, G. ;
Schoels, L. ;
Buerk, K. ;
de Vos, R. A. ;
den Dunnen, W. ;
Bechmann, I. ;
Egensperger, R. ;
Van Broeckhoven, C. ;
Gierga, K. ;
Deller, T. ;
Rueb, U. .
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 2008, 34 (05) :479-491
[45]   A survey of spinocerebellar ataxia in South Brazil -: 66 new cases with Machado-Joseph disease, SCA7, SCA8, or unidentified disease -: Causing mutations [J].
Jardim, LB ;
Silveira, I ;
Pereira, ML ;
Ferro, A ;
Alonso, I ;
Moreira, MDC ;
Mendonça, P ;
Ferreirinha, F ;
Sequeiros, J ;
Giugliani, R .
JOURNAL OF NEUROLOGY, 2001, 248 (10) :870-876
[46]   Frequency of KCNC3 DNA Variants as Causes of Spinocerebellar Ataxia 13 (SCA13) [J].
Figueroa, Karla P. ;
Waters, Michael F. ;
Garibyan, Vartan ;
Bird, Thomas D. ;
Gomez, Christopher M. ;
Ranum, Laura P. W. ;
Minassian, Natali A. ;
Papazian, Diane M. ;
Pulst, Stefan M. .
PLOS ONE, 2011, 6 (03)
[47]   Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients [J].
LopesCendes, I ;
Teive, HGA ;
Calcagnotto, ME ;
DaCosta, JC ;
Cardoso, F ;
Viana, E ;
Maciel, JA ;
Radvany, J ;
Arruda, WO ;
TrevisolBittencourt, PC ;
Neto, PR ;
Silveira, I ;
Steiner, CE ;
Pinto, W ;
Santos, AS ;
Neto, YC ;
Werneck, LC ;
Araujo, AQC ;
Carakushansky, G ;
Mello, LR ;
Jardim, LB ;
Rouleau, GA .
ARQUIVOS DE NEURO-PSIQUIATRIA, 1997, 55 (3B) :519-529
[48]   Spinocerebellar ataxia type 6 (SCA6): neurodegeneration goes beyond the known brain predilection sites [J].
Gierga, K. ;
Schelhaas, H. J. ;
Brunt, E. R. ;
Seidel, K. ;
Scherzed, W. ;
Egensperger, R. ;
de Vos, R. A. I. ;
den Dunnen, W. ;
Ippel, P. F. ;
Petrasch-Parwez, E. ;
Deller, T. ;
Schoels, L. ;
Rueb, U. .
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 2009, 35 (05) :515-527
[49]   Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications [J].
Cendelin, Jan ;
Cvetanovic, Marija ;
Gandelman, Mandi ;
Hirai, Hirokazu ;
Orr, Harry T. ;
Pulst, Stefan M. ;
Strupp, Michael ;
Tichanek, Filip ;
Tuma, Jan ;
Manto, Mario .
CEREBELLUM, 2022, 21 (03) :452-481
[50]   Chronic suppression of STIM1-mediated calcium signaling in Purkinje cells rescues the cerebellar pathology in spinocerebellar ataxia type 2 [J].
Egorova, Polina A. ;
Marinina, Ksenia S. ;
Bezprozvanny, Ilya B. .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2023, 1870 (05)