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Entry Name Spinocerebellar ataxia
Description The autosomal dominant spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative diseases characterised by loss of balance and motor coordination due to the primary dysfunction of the cerebellum. Compelling evidence points to major aetiological roles for transcriptional dysregulation, protein aggregation and clearance, autophagy, the ubiquitin-proteasome system, alterations of calcium homeostasis, mitochondria defects, toxic RNA gain-of-function mechanisms and eventual cell death with apoptotic features of neurons during SCA disease progression.
Class Human Diseases; Neurodegenerative diseaseBRITE hierarchy
Pathway map Disease H00063 Spinocerebellar ataxia (SCA)
Orthology K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K03028 PSMD2, RPN1; 26S proteasome regulatory subunit N1
K03029 PSMD4, RPN10; 26S proteasome regulatory subunit N10
K03030 PSMD14, RPN11, POH1; 26S proteasome regulatory subunit N11
K03031 PSMD8, RPN12; 26S proteasome regulatory subunit N12
K03032 PSMD1, RPN2; 26S proteasome regulatory subunit N2
K03033 PSMD3, RPN3; 26S proteasome regulatory subunit N3
K03035 PSMD12, RPN5; 26S proteasome regulatory subunit N5
K03036 PSMD11, RPN6; 26S proteasome regulatory subunit N6
K03037 PSMD6, RPN7; 26S proteasome regulatory subunit N7
K03038 PSMD7, RPN8; 26S proteasome regulatory subunit N8
K03039 PSMD13, RPN9; 26S proteasome regulatory subunit N9
K03061 PSMC2, RPT1; 26S proteasome regulatory subunit T1
K03062 PSMC1, RPT2; 26S proteasome regulatory subunit T2
K03063 PSMC4, RPT3; 26S proteasome regulatory subunit T3
K03064 PSMC6, RPT4; 26S proteasome regulatory subunit T4
K03065 PSMC3, RPT5; 26S proteasome regulatory subunit T5
K03066 PSMC5, RPT6; 26S proteasome regulatory subunit T6
K03120 TBP; transcription initiation factor TFIID TATA-box-binding protein
K03124 TFIIB, GTF2B, SUA7, tfb; transcription initiation factor TFIIB
K04344 CACNA1A, CAV2.1; voltage-dependent calcium channel P/Q type alpha-1A
K04426 MAP3K5, ASK1; mitogen-activated protein kinase kinase kinase 5 [EC:2.7.11.25 ]
K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24 ]
K04603 GRM1; metabotropic glutamate receptor 1
K04634 GNAQ; guanine nucleotide-binding protein G(q) subunit alpha
K04684 SP1; transcription factor Sp1
K04889 KCNC3, KV3.3; potassium voltage-gated channel Shaw-related subfamily C member 3
K04893 KCND3, KV4.3; potassium voltage-gated channel Shal-related subfamily D member 3
K04958 ITPR1; inositol 1,4,5-triphosphate receptor type 1
K04959 ITPR2; inositol 1,4,5-triphosphate receptor type 2
K04960 ITPR3; inositol 1,4,5-triphosphate receptor type 3
K04961 RYR1; ryanodine receptor 1
K04966 TRPC3; transient receptor potential cation channel subfamily C member 3
K05197 GRIA1; glutamate receptor 1
K05198 GRIA2; glutamate receptor 2
K05199 GRIA3; glutamate receptor 3
K05208 GRIN1; glutamate receptor ionotropic, NMDA 1
K05209 GRIN2A; glutamate receptor ionotropic, NMDA 2A
K05210 GRIN2B; glutamate receptor ionotropic, NMDA 2B
K05211 GRIN2C; glutamate receptor ionotropic, NMDA 2C
K05212 GRIN2D; glutamate receptor ionotropic, NMDA 2D
K05213 GRIN3A; glutamate receptor ionotropic, NMDA 3A
K05214 GRIN3B; glutamate receptor ionotropic, NMDA 3B
K05617 SLC1A6, EAAT4; solute carrier family 1 (high affinity glutamate/aspartate transporter), member 6
K05862 VDAC1; voltage-dependent anion channel protein 1
K05863 SLC25A4S, ANT; solute carrier family 25 (mitochondrial adenine nucleotide translocator), member 4/5/6/31
K06053 RBPSUH, RBPJK; recombining binding protein suppressor of hairless
K06249 RELN; reelin [EC:3.4.21.-]
K06691 RPN13; 26S proteasome regulatory subunit N13
K06693 PSMD9, RPN4; 26S proteasome regulatory subunit N4
K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1 ]
K08064 NFYA, HAP2; nuclear transcription factor Y, alpha
K08331 ATG13; autophagy-related protein 13
K08333 PIK3R4, VPS15; phosphoinositide-3-kinase, regulatory subunit 4 [EC:2.7.11.1 ]
K08334 BECN, VPS30, ATG6; beclin
K08532 NR1F1, RORA; RAR-related orphan receptor alpha
K08852 ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 [EC:2.7.11.1 3.1.26.-]
K08956 AFG3; AFG3 family protein [EC:3.4.24.-]
K09027 XBP1; X box-binding protein 1
K09064 MYOD1, MYF3; myogenic factor 3
K09565 PPIF; peptidyl-prolyl isomerase F (cyclophilin D) [EC:5.2.1.8 ]
K10881 SHFM1, DSS1, RPN15; 26 proteasome complex subunit DSS1
K11304 TIP60, KAT5, ESA1; histone acetyltransferase HTATIP [EC:2.3.1.48 ]
K11863 ATXN3, MJD; Ataxin-3 [EC:3.4.22.-]
K14564 NOP56; nucleolar protein 56
K15040 VDAC2; voltage-dependent anion channel protein 2
K15041 VDAC3; voltage-dependent anion channel protein 3
K15840 PDYN, PENKB; proenkephalin B (prodynorphin)
K17589 RB1CC1; RB1-inducible coiled-coil protein 1
K17889 ATG14L, ATG14; beclin 1-associated autophagy-related key regulator
K17906 ATG2; autophagy-related protein 2
K17908 WIPI1_2, ATG18; autophagy-related protein 18
K17943 PUM; pumilio RNA-binding family
K17985 AMBRA1; activating molecule in BECN1-regulated autophagy protein 1
K19730 ATG101; autophagy-related protein 101
K20053 VLDLR; very low-density lipoprotein receptor
K20054 DAB1; disabled homolog 1
K20225 CIC; capicua transcriptional repressor
K20858 MCU; calcium uniporter protein, mitochondrial
K21246 NRBF2; nuclear receptor-binding factor 2
K23010 OMA1; metalloendopeptidase OMA1, mitochondrial
K23920 FGF14, FHF4; fibroblast growth factor 14
K23932 SPTBN2; spectrin beta, non-erythrocytic 2
K23933 ATXN8OS; ATXN8 opposite strand lncRNA
Compound C01245 D-myo-Inositol 1,4,5-trisphosphate
C04549 1-Phosphatidyl-1D-myo-inositol 3-phosphate
Reference Authors Matilla-Duenas A, Sanchez I, Corral-Juan M, Davalos A, Alvarez R, Latorre P
Title Cellular and molecular pathways triggering neurodegeneration in the spinocerebellar ataxias.
Journal Reference Authors Duenas AM, Goold R, Giunti P
Title Molecular pathogenesis of spinocerebellar ataxias.
Journal Reference Authors Mark MD, Schwitalla JC, Groemmke M, Herlitze S
Title Keeping Our Calcium in Balance to Maintain Our Balance.
Journal Reference Authors Egorova PA, Bezprozvanny IB
Title Inositol 1,4,5-trisphosphate receptors and neurodegenerative disorders.
Journal Reference Authors Shimobayashi E, Kapfhammer JP
Title Calcium Signaling, PKC Gamma, IP3R1 and CAR8 Link Spinocerebellar Ataxias and Purkinje Cell Dendritic Development.
Journal Reference Authors Kasumu A, Bezprozvanny I
Title Deranged calcium signaling in Purkinje cells and pathogenesis in spinocerebellar ataxia 2 (SCA2) and other ataxias.
Journal Reference Authors Egorova P, Popugaeva E, Bezprozvanny I
Title Disturbed calcium signaling in spinocerebellar ataxias and Alzheimer's disease.
Journal Reference Authors Hisatsune C, Hamada K, Mikoshiba K
Title Ca(2+) signaling and spinocerebellar ataxia.
Journal Reference Authors Takada SH, Ikebara JM, de Sousa E, Cardoso DS, Resende RR, Ulrich H, Ruckl M, Rudiger S, Kihara AH
Title Determining the Roles of Inositol Trisphosphate Receptors in Neurodegeneration: Interdisciplinary Perspectives on a Complex Topic.
Journal Reference Authors Brown SA, Loew LM
Title Integration of modeling with experimental and clinical findings synthesizes and refines the central role of inositol 1,4,5-trisphosphate receptor 1 in spinocerebellar ataxia.
Journal Reference Authors Inoue T
Title Dynamics of calcium and its roles in the dendrite of the cerebellar Purkinje cell.
Journal Reference Authors Adachi N, Kobayashi T, Takahashi H, Kawasaki T, Shirai Y, Ueyama T, Matsuda T, Seki T, Sakai N, Saito N
Title Enzymological analysis of mutant protein kinase Cgamma causing spinocerebellar ataxia type 14 and dysfunction in Ca2+ homeostasis.
Journal Reference Authors Smeets CJ, Jezierska J, Watanabe H, Duarri A, Fokkens MR, Meijer M, Zhou Q, Yakovleva T, Boddeke E, den Dunnen W, van Deursen J, Bakalkin G, Kampinga HH, van de Sluis B, Verbeek DS
Title Elevated mutant dynorphin A causes Purkinje cell loss and motor dysfunction in spinocerebellar ataxia type 23.
Journal Reference Authors Tulli S, Del Bondio A, Baderna V, Mazza D, Codazzi F, Pierson TM, Ambrosi A, Nolte D, Goizet C, Toro C, Baets J, Deconinck T, DeJonghe P, Mandich P, Casari G, Maltecca F
Title Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation.
Journal Reference Authors Mancini C, Hoxha E, Iommarini L, Brussino A, Richter U, Montarolo F, Cagnoli C, Parolisi R, Gondor Morosini DI, Nicolo V, Maltecca F, Muratori L, Ronchi G, Geuna S, Arnaboldi F, Donetti E, Giorgio E, Cavalieri S, Di Gregorio E, Pozzi E, Ferrero M, Riberi E, Casari G, Altruda F, Turco E, Gasparre G, Battersby BJ, Porcelli AM, Ferrero E, Brusco A, Tempia F
Title Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity.
Journal Reference Authors Becker EBE
Title From Mice to Men: TRPC3 in Cerebellar Ataxia.
Journal Reference Authors Hoxha E, Tempia F, Lippiello P, Miniaci MC
Title Modulation, Plasticity and Pathophysiology of the Parallel Fiber-Purkinje Cell Synapse.
Journal Reference Authors Yan H, Pablo JL, Pitt GS
Title FGF14 regulates presynaptic Ca2+ channels and synaptic transmission.
Journal Reference Authors Tada M, Nishizawa M, Onodera O
Title Roles of inositol 1,4,5-trisphosphate receptors in spinocerebellar ataxias.
Journal Reference Authors Pietrobon D
Title CaV2.1 channelopathies.
Journal Reference Authors Matsuyama Z, Yanagisawa NK, Aoki Y, Black JL 3rd, Lennon VA, Mori Y, Imoto K, Inuzuka T
Title Polyglutamine repeats of spinocerebellar ataxia 6 impair the cell-death-preventing effect of CaV2.1 Ca2+ channel--loss-of-function cellular model of SCA6.
Journal Reference Authors Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H
Title ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats.
Journal Reference Authors Evers MM, Toonen LJ, van Roon-Mom WM
Title Ataxin-3 protein and RNA toxicity in spinocerebellar ataxia type 3: current insights and emerging therapeutic strategies.
Journal Reference Authors Ashkenazi A, Bento CF, Ricketts T, Vicinanza M, Siddiqi F, Pavel M, Squitieri F, Hardenberg MC, Imarisio S, Menzies FM, Rubinsztein DC
Title Polyglutamine tracts regulate autophagy.
Journal Reference Authors Chen RH, Chen YH, Huang TY
Title Ubiquitin-mediated regulation of autophagy.
Journal Reference Authors Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N, Lysholm A, Burright E, Zoghbi HY, Clark HB, Andresen JM, Orr HT
Title RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice.
Journal Reference Authors Rousseaux MWC, Tschumperlin T, Lu HC, Lackey EP, Bondar VV, Wan YW, Tan Q, Adamski CJ, Friedrich J, Twaroski K, Chen W, Tolar J, Henzler C, Sharma A, Bajic A, Lin T, Duvick L, Liu Z, Sillitoe RV, Zoghbi HY, Orr HT
Title ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism.
Journal Reference Authors Jimenez G, Shvartsman SY, Paroush Z
Title The Capicua repressor--a general sensor of RTK signaling in development and disease.
Journal Reference Authors Gennarino VA, Palmer EE, McDonell LM, Wang L, Adamski CJ, Koire A, See L, Chen CA, Schaaf CP, Rosenfeld JA, Panzer JA, Moog U, Hao S, Bye A, Kirk EP, Stankiewicz P, Breman AM, McBride A, Kandula T, Dubbs HA, Macintosh R, Cardamone M, Zhu Y, Ying K, Dias KR, Cho MT, Henderson LB, Baskin B, Morris P, Tao J, Cowley MJ, Dinger ME, Roscioli T, Caluseriu O, Suchowersky O, Sachdev RK, Lichtarge O, Tang J, Boycott KM, Holder JL Jr, Zoghbi HY
Title A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.
Journal Reference Authors Irie T, Matsuzaki Y, Sekino Y, Hirai H
Title Kv3.3 channels harbouring a mutation of spinocerebellar ataxia type 13 alter excitability and induce cell death in cultured cerebellar Purkinje cells.
Journal Reference Authors Bushart DD, Murphy GG, Shakkottai VG
Title Precision medicine in spinocerebellar ataxias: treatment based on common mechanisms of disease.
Journal Reference Authors Hsiao CT, Fu SJ, Liu YT, Lu YH, Zhong CY, Tang CY, Soong BW, Jeng CJ
Title Novel SCA19/22-associated KCND3 mutations disrupt human KV 4.3 protein biosynthesis and channel gating.
Journal Reference Authors Duarri A, Lin MC, Fokkens MR, Meijer M, Smeets CJ, Nibbeling EA, Boddeke E, Sinke RJ, Kampinga HH, Papazian DM, Verbeek DS
Title Spinocerebellar ataxia type 19/22 mutations alter heterocomplex Kv4.3 channel function and gating in a dominant manner.
Journal Reference Authors Matilla-Duenas A, Volpini V
Title Spinocerebellar Ataxia Type 37
Journal GeneReviews (1993)
Reference Authors Corral-Juan M, Serrano-Munuera C, Rabano A, Cota-Gonzalez D, Segarra-Roca A, Ispierto L, Cano-Orgaz AT, Adarmes AD, Mendez-Del-Barrio C, Jesus S, Mir P, Volpini V, Alvarez-Ramo R, Sanchez I, Matilla-Duenas A
Title Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.
Journal Reference Authors Swinnen B, Robberecht W, Van Den Bosch L
Title RNA toxicity in non-coding repeat expansion disorders.
Journal Reference Authors Ishikawa K, Nagai Y
Title Molecular Mechanisms and Future Therapeutics for Spinocerebellar Ataxia Type 31 (SCA31).
Journal Reference Authors Niimi Y, Takahashi M, Sugawara E, Umeda S, Obayashi M, Sato N, Ishiguro T, Higashi M, Eishi Y, Mizusawa H, Ishikawa K
Title Abnormal RNA structures (RNA foci) containing a penta-nucleotide repeat (UGGAA)n in the Purkinje cell nucleus is associated with spinocerebellar ataxia type 31 pathogenesis.
Journal Reference Authors Kobayashi H, Abe K, Matsuura T, Ikeda Y, Hitomi T, Akechi Y, Habu T, Liu W, Okuda H, Koizumi A
Title Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement.
Journal Related ko04141 Protein processing in endoplasmic reticulum
