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Entry
Name
Spinocerebellar ataxia - Mus musculus (house mouse)
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 disease
BRITE hierarchy
Pathway map
Ortholog table
Organism
Mus musculus (house mouse) [GN:
mmu ]
Gene
22065 Trpc3; transient receptor potential cation channel, subfamily C, member 3 [KO:K04966 ]
14816 Grm1; glutamate receptor, metabotropic 1 [KO:K04603 ]
14682 Gnaq; guanine nucleotide binding protein, alpha q polypeptide [KO:K04634 ]
14799 Gria1; glutamate receptor, ionotropic, AMPA1 (alpha 1) [KO:K05197 ]
14800 Gria2; glutamate receptor, ionotropic, AMPA2 (alpha 2) [KO:K05198 ]
53623 Gria3; glutamate receptor, ionotropic, AMPA3 (alpha 3) [KO:K05199 ]
12286 Cacna1a; calcium channel, voltage-dependent, P/Q type, alpha 1A subunit [KO:K04344 ]
16438 Itpr1; inositol 1,4,5-trisphosphate receptor 1 [KO:K04958 ]
16439 Itpr2; inositol 1,4,5-triphosphate receptor 2 [KO:K04959 ]
16440 Itpr3; inositol 1,4,5-triphosphate receptor 3 [KO:K04960 ]
20190 Ryr1; ryanodine receptor 1, skeletal muscle [KO:K04961 ]
14810 Grin1; glutamate receptor, ionotropic, NMDA1 (zeta 1) [KO:K05208 ]
14811 Grin2a; glutamate receptor, ionotropic, NMDA2A (epsilon 1) [KO:K05209 ]
14812 Grin2b; glutamate receptor, ionotropic, NMDA2B (epsilon 2) [KO:K05210 ]
14813 Grin2c; glutamate receptor, ionotropic, NMDA2C (epsilon 3) [KO:K05211 ]
14814 Grin2d; glutamate receptor, ionotropic, NMDA2D (epsilon 4) [KO:K05212 ]
242443 Grin3a; glutamate receptor ionotropic, NMDA3A [KO:K05213 ]
170483 Grin3b; glutamate receptor, ionotropic, NMDA3B [KO:K05214 ]
22333 Vdac1; voltage-dependent anion channel 1 [KO:K05862 ]
22334 Vdac2; voltage-dependent anion channel 2 [KO:K15040 ]
22335 Vdac3; voltage-dependent anion channel 3 [KO:K15041 ]
11739 Slc25a4; solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 4 [KO:K05863 ]
11740 Slc25a5; solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 5 [KO:K05863 ]
73333 Slc25a31; solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 31 [KO:K05863 ]
69597 Afg3l2; AFG3-like AAA ATPase 2 [KO:K08956 ] [EC:3.4.24.-]
114896 Afg3l1; AFG3-like AAA ATPase 1 [KO:K08956 ] [EC:3.4.24.-]
67013 Oma1; OMA1 zinc metallopeptidase [KO:K23010 ] [EC:3.4.24.-]
20743 Sptbn2; spectrin beta, non-erythrocytic 2 [KO:K23932 ]
19181 Psmc2; proteasome (prosome, macropain) 26S subunit, ATPase 2 [KO:K03061 ]
19179 Psmc1; protease (prosome, macropain) 26S subunit, ATPase 1 [KO:K03062 ]
23996 Psmc4; proteasome (prosome, macropain) 26S subunit, ATPase, 4 [KO:K03063 ]
67089 Psmc6; proteasome (prosome, macropain) 26S subunit, ATPase, 6 [KO:K03064 ]
19182 Psmc3; proteasome (prosome, macropain) 26S subunit, ATPase 3 [KO:K03065 ]
19184 Psmc5; protease (prosome, macropain) 26S subunit, ATPase 5 [KO:K03066 ]
21762 Psmd2; proteasome (prosome, macropain) 26S subunit, non-ATPase, 2 [KO:K03028 ]
70247 Psmd1; proteasome (prosome, macropain) 26S subunit, non-ATPase, 1 [KO:K03032 ]
22123 Psmd3; proteasome (prosome, macropain) 26S subunit, non-ATPase, 3 [KO:K03033 ]
67151 Psmd9; proteasome (prosome, macropain) 26S subunit, non-ATPase, 9 [KO:K06693 ]
66997 Psmd12; proteasome (prosome, macropain) 26S subunit, non-ATPase, 12 [KO:K03035 ]
69077 Psmd11; proteasome (prosome, macropain) 26S subunit, non-ATPase, 11 [KO:K03036 ]
66413 Psmd6; proteasome (prosome, macropain) 26S subunit, non-ATPase, 6 [KO:K03037 ]
17463 Psmd7; proteasome (prosome, macropain) 26S subunit, non-ATPase, 7 [KO:K03038 ]
23997 Psmd13; proteasome (prosome, macropain) 26S subunit, non-ATPase, 13 [KO:K03039 ]
19185 Psmd4; proteasome (prosome, macropain) 26S subunit, non-ATPase, 4 [KO:K03029 ]
59029 Psmd14; proteasome (prosome, macropain) 26S subunit, non-ATPase, 14 [KO:K03030 ]
57296 Psmd8; proteasome (prosome, macropain) 26S subunit, non-ATPase, 8 [KO:K03031 ]
56436 Adrm1; adhesion regulating molecule 1 26S proteasome ubiquitin receptor [KO:K06691 ]
20422 Sem1; SEM1, 26S proteasome complex subunit [KO:K10881 ]
19883 Rora; RAR-related orphan receptor alpha [KO:K08532 ]
11937 Atp2a1; ATPase, Ca++ transporting, cardiac muscle, fast twitch 1 [KO:K05853 ] [EC:7.2.2.10 ]
11938 Atp2a2; ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 [KO:K05853 ] [EC:7.2.2.10 ]
20513 Slc1a6; solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6 [KO:K05617 ]
71722 Cic; capicua transcriptional repressor [KO:K20225 ]
80912 Pum1; pumilio RNA-binding family member 1 [KO:K17943 ]
80913 Pum2; pumilio RNA-binding family member 2 [KO:K17943 ]
19664 Rbpj; recombination signal binding protein for immunoglobulin kappa J region [KO:K06053 ]
19668 Rbpjl; recombination signal binding protein for immunoglobulin kappa J region-like [KO:K06053 ]
20683 Sp1; trans-acting transcription factor 1 [KO:K04684 ]
18044 Nfya; nuclear transcription factor-Y alpha [KO:K08064 ]
52639 Wipi1; WD repeat domain, phosphoinositide interacting 1 [KO:K17908 ]
74781 Wipi2; WD repeat domain, phosphoinositide interacting 2 [KO:K17908 ]
16504 Kcnc3; potassium voltage gated channel, Shaw-related subfamily, member 3 [KO:K04889 ]
56543 Kcnd3; potassium voltage-gated channel, Shal-related family, member 3 [KO:K04893 ]
22359 Vldlr; very low density lipoprotein receptor [KO:K20053 ]
18706 Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922 ] [EC:2.7.1.153 ]
18707 Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
74769 Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922 ] [EC:2.7.1.153 ]
18709 Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
18708 Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
18710 Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
65115 Bean1; brain expressed, associated with Nedd4, 1 [KO:K19324 ]
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 pathway
mmu04141 Protein processing in endoplasmic reticulum
KO pathway
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