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.
引用
收藏
页数:28
相关论文
共 50 条
[21]   Spinocerebellar Ataxia 3 (SCA3) Patient with Peripheral Neuropathy [J].
Aminah, Siti ;
Pusparini, Lin ;
Lailiyya, Nushrotul ;
Ganiem, Ahrnad Rizal ;
Gamayani, Uni ;
Wibisono, Yusuf ;
Huda, Fathul ;
Sribudiani, Yunia ;
Achmad, Tri Hanggono .
MAJALAH KEDOKTERAN BANDUNG-MKB-BANDUNG MEDICAL JOURNAL, 2022, 54 (01) :57-62
[22]   Molecular physiopathology of the spinocerebellar ataxia type 6 (SCA6) [J].
Cervantes-Kardasch, VH ;
García-Martínez, E .
REVISTA DE INVESTIGACION CLINICA-CLINICAL AND TRANSLATIONAL INVESTIGATION, 2004, 56 (03) :368-374
[23]   Analysis of trinucleotide repeats in different SCA loci in spinocerebellar ataxia patients and in normal population of Taiwan [J].
Tsai, HF ;
Liu, CS ;
Leu, TM ;
Wen, FC ;
Lin, SJ ;
Liu, CC ;
Yang, DK ;
Li, C ;
Hsieh, M .
ACTA NEUROLOGICA SCANDINAVICA, 2004, 109 (05) :355-360
[24]   Spinocerebellar Ataxia Type 13 is an Uncommon SCA Subtype in the Chinese Han Population [J].
Peng, Lan ;
Wang, Chunrong ;
Chen, Zhao ;
Wang, Jun-Ling ;
Tang, Bei-Sha ;
Jiang, Hong .
INTERNATIONAL JOURNAL OF NEUROSCIENCE, 2013, 123 (07) :450-453
[25]   Spinocerebellar ataxia type 23 is an uncommon SCA subtype in the Chinese Han population [J].
Liu, Yu-Tao ;
Tang, Bei-Sha ;
Wang, Jun-Ling ;
Guan, Wen-Juan ;
Shen, Lu ;
Shi, Yu-Ting ;
Zhou, Ying ;
Yan, Xin-Xiang ;
Xia, Kun ;
Jiang, Hong .
NEUROSCIENCE LETTERS, 2012, 528 (01) :51-54
[26]   Spinocerebellar Ataxia Type 6: Molecular Mechanisms and Calcium Channel Genetics [J].
Du, Xiaofei ;
Gomez, Christopher Manuel .
POLYGLUTAMINE DISORDERS, 2018, 1049 :147-173
[27]   Spinocerebellar ataxia type 1 (SCA1): new pathoanatomical and clinico-pathological insights [J].
Rueb, U. ;
Buerk, K. ;
Timmann, D. ;
den Dunnen, W. ;
Seidel, K. ;
Farrag, K. ;
Brunt, E. ;
Heinsen, H. ;
Egensperger, R. ;
Bornemann, A. ;
Schwarzacher, S. ;
Korf, H. -W. ;
Schoels, L. ;
Bohl, J. ;
Deller, T. .
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 2012, 38 (07) :665-680
[28]   Simplified Model of PKCγ Signaling Dysregulation and Cytosol-to-Membrane Translocation Kinetics During Neurodegenerative Spinocerebellar Ataxia Type 14 (SCA14) [J].
Aslam, Naveed ;
Alvi, Farah .
FRONTIERS IN NEUROSCIENCE, 2020, 13
[29]   A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2 [J].
Meera, Pratap ;
Pulst, Stefan ;
Otis, Thomas .
ELIFE, 2017, 6
[30]   Spinocerebellar ataxia type 14 (SCA14) in an Argentinian family: a case report [J].
Duggirala, Niharika ;
Ngo, Kathie J. J. ;
Pagnoni, Sabrina M. M. ;
Rosa, Alberto L. L. ;
Fogel, Brent L. L. .
JOURNAL OF MEDICAL CASE REPORTS, 2023, 17 (01)