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Defective cerebellar ryanodine receptor type 1 and endoplasmic reticulum calcium ‘leak’ in tremor pathophysiology

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Abstract

Essential Tremor (ET) is a prevalent neurological disease characterized by an 8–10 Hz action tremor. Molecular mechanisms of ET remain poorly understood. Clinical data suggest the importance of the cerebellum in disease pathophysiology, and pathological studies indicate Purkinje Cells (PCs) incur damage. Our recent cerebellar cortex and PC-specific transcriptome studies identified alterations in calcium (Ca2+) signaling pathways that included ryanodine receptor type 1 (RyR1) in ET. RyR1 is an intracellular Ca2+ release channel located on the Endoplasmic Reticulum (ER), and in cerebellum is predominantly expressed in PCs. Under stress conditions, RyR1 undergoes several post-translational modifications (protein kinase A [PKA] phosphorylation, oxidation, nitrosylation), coupled with depletion of the channel-stabilizing binding partner calstabin1, which collectively characterize a “leaky channel” biochemical signature. In this study, we found markedly increased PKA phosphorylation at the RyR1-S2844 site, increased RyR1 oxidation and nitrosylation, and calstabin1 depletion from the RyR1 complex in postmortem ET cerebellum. Decreased calstabin1-RyR1-binding affinity correlated with loss of PCs and climbing fiber-PC synapses in ET. This ‘leaky’ RyR1 signature was not seen in control or Parkinson’s disease cerebellum. Microsomes from postmortem cerebellum demonstrated excessive ER Ca2+ leak in ET vs. controls, attenuated by channel stabilization. We further studied the role of RyR1 in tremor using a mouse model harboring a RyR1 point mutation that mimics constitutive site-specific PKA phosphorylation (RyR1-S2844D). RyR1-S2844D homozygous mice develop a 10 Hz action tremor and robust abnormal oscillatory activity in cerebellar physiological recordings. Intra-cerebellar microinfusion of RyR1 agonist or antagonist, respectively, increased or decreased tremor amplitude in RyR1-S2844D mice, supporting a direct role of cerebellar RyR1 leakiness for tremor generation. Treating RyR1-S2844D mice with a novel RyR1 channel-stabilizing compound, Rycal, effectively dampened cerebellar oscillatory activity, suppressed tremor, and normalized cerebellar RyR1-calstabin1 binding. These data collectively support that stress-associated ER Ca2+ leak via RyR1 may contribute to tremor pathophysiology.

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References

  1. Abu-Omar N, Das J, Szeto V, Feng ZP (2018) Neuronal ryanodine receptors in development and aging. Mol Neurobiol 55(2):1183–1192. https://doi.org/10.1007/s12035-016-0375-4

    Article  CAS  PubMed  Google Scholar 

  2. Almeida Lopes ACB, Peixe TS, Mesas AE, Paoliello MMB (2016) Lead exposure and oxidative stress: a systematic review. Rev Environ Contam Toxicol 236:193–238. https://doi.org/10.1007/978-3-319-20013-2_3

    Article  CAS  Google Scholar 

  3. Andersson DC, Betzenhauser MJ, Reiken S, Meli AC, Umanskaya A, Xie W et al (2011) Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. Cell Metab 14(2):196–207. https://doi.org/10.1016/j.cmet.2011.05.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Babij R, Lee M, Cortes E, Vonsattel JP, Faust PL, Louis ED (2013) Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain 136(Pt 10):3051–3061. https://doi.org/10.1093/brain/awt238

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bellinger AM, Reiken S, Carlson C, Mongillo M, Liu X, Rothman L et al (2009) Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 15(3):325–330. https://doi.org/10.1038/nm.1916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Benito-Leon J, Labiano-Fontcuberta A (2016) Linking essential tremor to the cerebellum: clinical evidence. Cerebellum 15(3):253–262. https://doi.org/10.1007/s12311-015-0741-1

    Article  PubMed  Google Scholar 

  7. Bezprozvanny I, Watras J, Ehrlich BE (1991) Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 351:751–754. https://doi.org/10.1038/351751a0

    Article  CAS  PubMed  Google Scholar 

  8. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112(4):389–404. https://doi.org/10.1007/s00401-006-0127-z

    Article  PubMed  PubMed Central  Google Scholar 

  9. Braak H, Braak E (1997) Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 18:S85–S88. https://doi.org/10.1016/s0197-4580(97)00062-6

    Article  CAS  PubMed  Google Scholar 

  10. Cerasa A, Quattrone A (2016) Linking essential tremor to the cerebellum-neuroimaging evidence. Cerebellum 15(3):263–275. https://doi.org/10.1007/s12311-015-0739-8

    Article  CAS  PubMed  Google Scholar 

  11. Choe M, Cortes E, Vonsattel JP, Kuo SH, Faust PL, Louis ED (2016) Purkinje cell loss in essential tremor: random sampling quantification and nearest neighbor analysis. Mov Disord 31(3):393–401. https://doi.org/10.1002/mds.26490

    Article  PubMed  PubMed Central  Google Scholar 

  12. Clodfelter GV, Porter NM, Landfield PW, Thibault O (2002) Sustained Ca 2+ −induced Ca 2+ −release underlies the postglutamate lethal Ca2+ plateau in older cultured hippocampal neurons. Eur J Pharmacol 447:189–200. https://doi.org/10.1016/s0014-2999(02)01843-5

    Article  CAS  PubMed  Google Scholar 

  13. De Zeeuw CI (2021) Bidirectional learning in upbound and downbound microzones of the cerebellum. Nat Rev Neurosci 22(2):92–110. https://doi.org/10.1038/s41583-020-00392-x

    Article  CAS  PubMed  Google Scholar 

  14. Dogu O, Louis ED, Tamer LT, Unal O, Yilmaz A, Kaleagasi H (2007) elevated blood lead concentrations in essential tremor: a case-control study in Mersin, Turkey. Environ Health Perspect 115(11):1564–1568. https://doi.org/10.1289/ehp.10352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dridi H, Liu X, Yuan Q, Reiken S, Yehia M, Sittenfeld L et al (2020) Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease. JCI Insight. https://doi.org/10.1172/jci.insight.140614

    Article  PubMed  PubMed Central  Google Scholar 

  16. Duenas AM, Goold R, Giunti P (2006) Molecular pathogenesis of spinocerebellar ataxias. Brain 129(Pt 6):1357–1370. https://doi.org/10.1093/brain/awl081

    Article  PubMed  Google Scholar 

  17. Egorova PA, Bezprozvanny IB (2022) Electrophysiological studies support utility of positive modulators of SK channels for the treatment of spinocerebellar ataxia type 2. Cerebellum 21(5):742–749. https://doi.org/10.1007/s12311-021-01349-1

    Article  CAS  PubMed  Google Scholar 

  18. Erickson-Davis CR, Faust PL, Vonsattel J-PG, Gupta S, Honig LS, Louis ED (2010) ‘“Hairy Baskets”’ associated with degenerative Purkinje cell changes in essential tremor. Neuropathol Exp Neurol 69(3):262–271. https://doi.org/10.1097/NEN.0b013e3181d1ad04

    Article  Google Scholar 

  19. Fierro L, Llano I (1996) High endogenous calcium buffering in Purkinje cells from rat cerebellar slices. J Physiol 496(3):617–625. https://doi.org/10.1113/jphysiol.1996.sp021713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fierro L, DiPolo R, Llano I (1998) Intracellular calcium clearance in Purkinje cell somata from rat cerebellar slices. J Physiol 510:499–512. https://doi.org/10.1111/j.1469-7793.1998.499bk.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Filip P, Lungu OV, Manto MU, Bares M (2016) Linking essential tremor to the cerebellum: physiological evidence. Cerebellum 15(6):774–780. https://doi.org/10.1007/s12311-015-0740-2

    Article  PubMed  Google Scholar 

  22. Giannini G, Conti A, Mammarella S, Scrobogna M, Sorrentino V (1995) The ryanodine receptor: calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. JCB 128(5):893–904. https://doi.org/10.1083/jcb.128.5.893

    Article  CAS  PubMed  Google Scholar 

  23. Gomez LC, Kawaguchi S-Y, Collin T, Jalil A, Del Pilar M, Gomez EN et al (2020) Influence of spatially segregated IP 3-producing pathways on spike generation and transmitter release in Purkinje cell axons. Proc Natl Acad Sci 117(20):11097–11108. https://doi.org/10.1073/pnas.2000148117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Haines DE, Dietrichs E (2012) The cerebellum—structure and connections. Handb Clin Neurol 103:3–36. https://doi.org/10.1016/B978-0-444-51892-7.00001-2

    Article  PubMed  Google Scholar 

  25. Hall T, Miller A, Corsellis J (1975) Variations in the human Purkinje cell population according to age and sex. Neuropathol Exp Neurol 1(3):267–292. https://doi.org/10.1111/j.1365-2990.1975.tb00652.x

    Article  Google Scholar 

  26. Haubenberger D, Abbruzzese G, Bain PG, Bajaj N, Benito-León J, Bhatia KP et al (2016) Transducer-based evaluation of tremor. Mov Disord 31(9):1327–1336

    Article  PubMed  PubMed Central  Google Scholar 

  27. Huang M, Verbeek DS (2019) Why do so many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia? Neurosci Lett 688:49–57. https://doi.org/10.1016/j.neulet.2018.02.004

    Article  CAS  PubMed  Google Scholar 

  28. Jayaraman T, Brillantes AM, Timerman AP, Fleischer S, Erdjument-Bromage H, Tempst P et al (1992) FK506 binding protein associated with the calcium release channel (ryanodine receptor). J Biol Chem 267(14):9474–9477. https://doi.org/10.1016/S0021-9258(19)50114-4

    Article  CAS  PubMed  Google Scholar 

  29. Jimenez-Jimenez FJ, Alonso-Navarro H, Garcia-Martin E, Alvarez I, Pastor P, Agundez JAG (2021) Genomic markers for essential tremor. Pharmaceuticals (Basel). https://doi.org/10.3390/ph14060516

    Article  PubMed  Google Scholar 

  30. Axelrad JE, Louis ED, Honig LS, Flores I, Ross W, Pahwa R et al (2008) Reduced Purkinje cell number in essential tremor: a postmortem study. Arch Neurol 65(1):101–107. https://doi.org/10.1001/archneurol.2007.8

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kakizawa S, Yamazawa T, Chen Y, Ito A, Murayama T, Oyamada H et al (2012) Nitric oxide-induced calcium release via ryanodine receptors regulates neuronal function. EMBO J 31(2):417–428. https://doi.org/10.1038/emboj.2011.386

    Article  CAS  PubMed  Google Scholar 

  32. Kakizawa S, Yamazawa T, Iino M (2013) Nitric oxide-induced calcium release: activation of type 1 ryanodine receptor by endogenous nitric oxide. Channels (Austin) 7(1):1–5. https://doi.org/10.4161/chan.22555

    Article  CAS  PubMed  Google Scholar 

  33. Khodakhah K, Armstrong CM (1997) Inositol trisphosphate and ryanodine receptors share a common functional Ca2+ pool in cerebellar Purkinje neurons. Biophys J 73(6):3349–3357. https://doi.org/10.1016/S0006-3495(97)78359-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kuo SH, Erickson-Davis C, Gillman A, Faust PL, Vonsattel JP, Louis ED (2011) Increased number of heterotopic Purkinje cells in essential tremor. JNNP 82(9):1038–1040. https://doi.org/10.1136/jnnp.2010.213330

    Article  Google Scholar 

  35. Kushnir A, Todd JJ, Witherspoon JW, Yuan Q, Reiken S, Lin H et al (2020) Intracellular calcium leak as a therapeutic target for RYR1-related myopathies. Acta Neuropathol 136(6):1089–1104. https://doi.org/10.1007/s00401-020-02150-w

    Article  CAS  Google Scholar 

  36. Kushnir A, Wajsberg B, Marks AR (2018) Ryanodine receptor dysfunction in human disorders. BBA-Mol Cell Res 1865(11 Pt B):1687–1697. https://doi.org/10.1016/j.bbamcr.2018.07.011

    Article  CAS  Google Scholar 

  37. Lacampagne A, Liu X, Reiken S, Bussiere R, Meli AC, Lauritzen I et al (2017) Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits. Acta Neuropathol 134(5):749–767. https://doi.org/10.1007/s00401-017-1733-7

    Article  CAS  PubMed  Google Scholar 

  38. Lawal TA, Todd JJ, Witherspoon JW, Bönnemann CG, Dowling JJ, Hamilton SL et al (2020) Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature. Skelet Muscle. https://doi.org/10.1186/s13395-020-00243-4

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lee D, Gan S, Faust P, Louis E, Kuo S (2018) Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes. Parkinsonism Relat Disord 51:24–29. https://doi.org/10.1016/j.parkreldis.2018.02.032

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lee PJ, Kerridge CA, Chatterjee D, Koeppen AH, Faust PL, Louis ED (2018) A quantitative study of empty baskets in essential tremor and other motor neurodegenerative diseases. J Neuropathol Exp Neurol. https://doi.org/10.1093/jnen/nly114

    Article  PubMed  PubMed Central  Google Scholar 

  41. Lenka A, Jankovic J (2021) Tremor syndromes: an updated review. Front Neurol. https://doi.org/10.3389/fneur.2021.684835

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lin C-Y, Louis ED, Faust PL, Koeppen AH, Vonsattel J-PG, Kuo S-H (2014) Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain 137:3149–3159. https://doi.org/10.1093/brain/awu281

    Article  PubMed  PubMed Central  Google Scholar 

  43. Liu J, Tang TS, Tu H, Nelson O, Herndon E, Huynh DP et al (2009) Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci 29(29):9148–9162. https://doi.org/10.1523/JNEUROSCI.0660-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu X, Betzenhauser MJ, Reiken S, Meli AC, Xie W, Chen B-X et al (2012) Role of leaky neuronal ryanodine receptors in stress- induced cognitive dysfunction. Cell 150(5):1055–1067. https://doi.org/10.1016/j.cell.2012.06.052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Louis ED (2013) The primary type of tremor in essential tremor is kinetic rather than postural: cross-sectional observation of tremor phenomenology in 369 cases. Eur J Neurol 20(4):725–727. https://doi.org/10.1111/j.1468-1331.2012.03855.x

    Article  CAS  PubMed  Google Scholar 

  46. Louis ED (2016) Linking essential tremor to the cerebellum: neuropathological evidence. Cerebellum 15(3):235–242. https://doi.org/10.1007/s12311-015-0692-6

    Article  PubMed  Google Scholar 

  47. Louis ED (2019) The roles of age and aging in essential tremor: an epidemiological perspective. Neuroepidemiology 52(1–2):111–118. https://doi.org/10.1159/000492831

    Article  PubMed  Google Scholar 

  48. Louis ED, Factor-Litvak P, Gerbin M, Slavkovich V, Graziano JH, Jiang W et al (2011) Blood harmane, blood lead, and severity of hand tremor: evidence of additive effects. Neurotoxicology 32:227–232. https://doi.org/10.1016/j.neuro.2010.12.002

    Article  CAS  PubMed  Google Scholar 

  49. Louis ED, Faust PL (2020) Essential tremor: the most common form of cerebellar degeneration? Cerebellum Ataxias 7(12):1–10. https://doi.org/10.1186/s40673-020-00121-1

    Article  Google Scholar 

  50. Louis ED, Faust PL (2020) Essential tremor pathology: neurodegeneration and reorganization of neuronal connections. Nat Rev Neurol 16(2):69–83. https://doi.org/10.1038/s41582-019-0302-1

    Article  CAS  PubMed  Google Scholar 

  51. Louis ED, Faust PL, Vonsattel JP, Honig LS, Rajput A, Rajput A et al (2009) Torpedoes in Parkinson’s disease, Alzheimer’s disease, essential tremor, and control brains. Mov Disord 24(11):1600–1605. https://doi.org/10.1002/mds.22567

    Article  PubMed  PubMed Central  Google Scholar 

  52. Louis ED, Faust PL, Vonsattel JP, Honig LS, Rajput A, Robinson CA et al (2007) Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 130(Pt 12):3297–3307. https://doi.org/10.1093/brain/awm266

    Article  PubMed  Google Scholar 

  53. Louis ED, Jurewicz EC, Applegate L, Factor-Litvak P, Parides M, Andrews L et al (2003) Association between essential tremor and blood lead concentration. Environ Health Perspect 111(14):1707–1711. https://doi.org/10.1289/ehp.6404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Louis ED, Kerridge CA, Chatterjee D, Martuscello RT, Diaz DT, Koeppen AH et al (2019) Contextualizing the pathology in the essential tremor cerebellar cortex: a patholog-omics approach. Acta Neuropathol 138(5):859–876. https://doi.org/10.1007/s00401-019-02043-7

    Article  PubMed  PubMed Central  Google Scholar 

  55. Louis ED, Kuo SH, Tate WJ, Kelly GC, Gutierrez J, Cortes EP et al (2018) Heterotopic Purkinje Cells: a Comparative Postmortem Study of Essential Tremor and Spinocerebellar Ataxias 1, 2, 3, and 6. Cerebellum 17(2):104–110. https://doi.org/10.1007/s12311-017-0876-3

    Article  PubMed  PubMed Central  Google Scholar 

  56. Louis ED, Lee M, Babij R, Ma K, Cortes E, Vonsattel JP et al (2014) Reduced Purkinje cell dendritic arborization and loss of dendritic spines in essential tremor. Brain 137(Pt 12):3142–3148. https://doi.org/10.1093/brain/awu314

    Article  PubMed  PubMed Central  Google Scholar 

  57. Louis ED, Martuscello RT, Gionco JT, Hartstone WG, Musacchio JB, Portenti M et al (2023) Histopathology of the cerebellar cortex in essential tremor and other neurodegenerative motor disorders: comparative analysis of 320 brains. Acta Neuropathol 145(3):265–283. https://doi.org/10.1007/s00401-022-02535-z

    Article  PubMed  Google Scholar 

  58. Louis ED, McCreary M (2021) How common is essential tremor? Update on the worldwide prevalence of essential tremor. TOHM. https://doi.org/10.5334/tohm.632

    Article  PubMed  PubMed Central  Google Scholar 

  59. Louis ED, Ottman R (2014) How many people in the USA have essential tremor? Deriving a population estimate based on epidemiological data. TOHM. https://doi.org/10.7916/D8TT4P4B

    Article  PubMed  PubMed Central  Google Scholar 

  60. Louis ED, Yi H, Erickson-Davis C, Vonsattel JP, Faust PL (2009) Structural study of Purkinje cell axonal torpedoes in essential tremor. Neurosci Lett 450(3):287–291. https://doi.org/10.1016/j.neulet.2008.11.043

    Article  CAS  PubMed  Google Scholar 

  61. Marks AR (1997) Intracellular calcium-release channels: regulators of cell life and death. Am J Physiol 2727(2):H597-605. https://doi.org/10.1152/ajpheart.1997.272.2.H597

    Article  Google Scholar 

  62. Martuscello RT, Kerridge CA, Chatterjee D, Hartstone WG, Kuo SH, Sims PA et al (2020) Gene expression analysis of the cerebellar cortex in essential tremor. Neurosci Lett 721:134540. https://doi.org/10.1016/j.neulet.2019.134540

    Article  CAS  PubMed  Google Scholar 

  63. Martuscello RT, Sivprakasam K, Hartstone WG, Kuo S-H, Konopka G, Louis ED et al (2022) Gene expression analysis of laser captured Purkinje cells in the essential tremor cerebellum. Cerebellum. https://doi.org/10.1007/s12311-022-01483-4

    Article  PubMed  Google Scholar 

  64. Marx S, Reiken S, Hisamatsu Y, Gaburjakova M, Gaburjakova J, Yang Y et al (2001) Phosphorylation-dependent regulation of ryanodine receptors: a novel role for leucine/isoleucine zippers. J Cell Biol 153(4):699–708. https://doi.org/10.1083/jcb.153.4.699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Marx S, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N et al (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101(4):365–376. https://doi.org/10.1016/s0092-8674(00)80847-8

    Article  CAS  PubMed  Google Scholar 

  66. Mirra SS (1997) The CERAD neuropathology protocol and consensus recommendations for the postmortem diagnosis of Alzheimer’s disease: a commentary. Neurobiol Aging 18:S91–S94. https://doi.org/10.1016/s0197-4580(97)00058-4

    Article  CAS  PubMed  Google Scholar 

  67. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW et al (2011) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123(1):1–11. https://doi.org/10.1007/s00401-011-0910-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mouton J, Marty I, Villaz M, Feltz A, Maulet Y (2001) Molecular interaction of dihydropyridine receptors with type-1 ryanodine receptors in rat brain. Biochem J 354:597–603. https://doi.org/10.1042/0264-6021:3540597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Odgerel Z, Hernandez N, Park J, Ottman R, Louis E, Clark L (2019) Whole genome sequencing and rare variant analysis in essential tremor families. PLoS ONE 14(8):e0220512. https://doi.org/10.1371/journal.pone.0220512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Otsu Y, Marcaggi P, Feltz A, Isope P, Kollo M, Nusser Z et al (2014) Activity-dependent gating of calcium spikes by A-type K+ channels controls climbing fiber signaling in Purkinje cell dendrites. Neuron 84(1):137–151. https://doi.org/10.1016/j.neuron.2014.08.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pan MK, Li YS, Wong SB, Ni CL, Wang YM, Liu WC et al (2020) Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology. Sci Transl Med 12(526):eaay1769. https://doi.org/10.1126/scitranslmed.aay1769

    Article  PubMed  PubMed Central  Google Scholar 

  72. Pchitskaya E, Popugaeva E, Bezprozvanny I (2018) Calcium signaling and molecular mechanisms underlying neurodegenerative diseases. Cell Calcium 70:87–94. https://doi.org/10.1016/j.ceca.2017.06.008

    Article  CAS  PubMed  Google Scholar 

  73. Prestori F, Moccia F, D’Angelo E (2019) Disrupted calcium signaling in animal models of human spinocerebellar ataxia (SCA). Int J Mol Sci. https://doi.org/10.3390/ijms21010216

    Article  PubMed  PubMed Central  Google Scholar 

  74. Reiken S, Lacampagne A, Zhou H, Kherani A, Lehnart SE, Ward C et al (2003) PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure. J Cell Biol 160(7):919–928. https://doi.org/10.1083/jcb.200211012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sammi SR, Agim ZS, Cannon JR (2018) Harmane-induced selective dopaminergic neurotoxicity in Caenorhabditis elegans. Toxicol Sci 161(2):335–348. https://doi.org/10.1093/toxsci/kfx223

    Article  CAS  PubMed  Google Scholar 

  76. Santulli G, Marks AR (2015) Essential roles of intracellular calcium release channels in muscle, brain, metabolism, and aging. Curr Mol Pharmacol 8(2):206–222. https://doi.org/10.2174/1874467208666150507105105

    Article  CAS  PubMed  Google Scholar 

  77. Thibault O, Gant JC, Landfield PW (2007) Expansion of the calcium hypothesis of brain aging and Alzheimer’s disease: minding the store. Aging Cell 6(3):307–317. https://doi.org/10.1111/j.1474-9726.2007.00295.x

    Article  CAS  PubMed  Google Scholar 

  78. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A et al (2015) Tissue-based map of the human proteome. Science. https://doi.org/10.1126/science.1260419

    Article  PubMed  Google Scholar 

  79. Vial F, Kassavetis P, Merchant S, Haubenberger D, Hallett M (2019) How to do an electrophysiological study of tremor. Clin Neurophysiol Pract 4:134–142. https://doi.org/10.1016/j.cnp.2019.06.002

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wilkins HM, Kirchhof D, Manning E, Joseph JW, Linseman DA (2013) Mitochondrial glutathione transport is a key determinant of neuronal susceptibility to oxidative and nitrosative stress. J Biol Chem 288(7):5091–5101. https://doi.org/10.1074/jbc.M112.405738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Womack MD, Walker JW, Khodakhah K (2000) Impaired calcium release in cerebellar Purkinje neurons maintained in culture. J Gen Physiol. https://doi.org/10.1085/jgp.115.3.339

    Article  PubMed  PubMed Central  Google Scholar 

  82. Yu M, Ma K, Faust PL, Honig LS, Cortes E, Vonsattel JP et al (2012) Increased number of Purkinje cell dendritic swellings in essential tremor. Eur J Neurol 19(4):625–630. https://doi.org/10.1111/j.1468-1331.2011.03598.x

    Article  CAS  PubMed  Google Scholar 

  83. Zalk R, Lehnart SE, Marks AR (2007) Modulation of the ryanodine receptor and intracellular calcium. Annu Rev Biochem 76:367–85. https://www.annualreviews.org/doi/https://doi.org/10.1146/annurev.biochem.76.053105.094237

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Acknowledgements

Human brain tissue was derived from the New York Brain Bank at Columbia University and the NIH NeuroBioBank (University of Miami, Miami FL; University of Maryland, Baltimore MD).

We would like to thank all the patients and families that contributed to brain donation and the staff at the ETCBR at the New York Brain Bank and the NIH NeuroBioBank. We thank Dr. Marco C. Miotti for creating the illustration of the RyR1 macromolecular complex of kinases, phosphatases, and accessory scaffold proteins.

Funding

Funding for this project was provided from the National Institutes of Health (NIH)/NINDS (R01 NS124854 [SHK and PLF], R01 NS118179 [SHK], R01 NS117745 [PLF and EDL], RF1 NS114570 [ARM], R01 NS104423 [SHK], R01 NS088257 [EDL], R01 NS086736 [EDL]; from the NIH/NHLBI (R25 HL156002 [ARM], R01 HL145473 [ARM], R01 HL140934 [ARM], R01 HL142903 [ARM], T32 HL120826 [ARM]) and from the NIH/NIDDK (R01 DK118240 [ARM]).

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Author notes

  1. Regina T. Martuscello and Meng-Ling Chen have contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Pathology and Cell Biology, Columbia University Medical Center Vagelos College of Physicians and Surgeons and the New York Presbyterian Hospital, 630 W 168th Street, PH Stem 15-124, New York, NY, 10032, USA

    Regina T. Martuscello & Phyllis L. Faust

  2. Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, 650 W 168th Street, BB305, New York, NY, USA

    Meng-Ling Chen, David S. Ruff, Chun-Lun Ni, Chih-Chun Lin & Sheng-Han Kuo

  3. Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, 1150 St Nicholas Ave, New York, NY, USA

    Steven Reiken, Leah R. Sittenfeld & Andrew R. Marks

  4. Initiative for Columbia Ataxia and Tremor, Columbia University, New York, NY, USA

    Regina T. Martuscello, Meng-Ling Chen, David S. Ruff, Chun-Lun Ni, Chih-Chun Lin, Ming-Kai Pan, Sheng-Han Kuo & Phyllis L. Faust

  5. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

    Ming-Kai Pan

  6. Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA

    Elan D. Louis

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  1. Regina T. Martuscello
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by RTM, M-LC, SR, LRS, DSR, C-LN, C-CL, M-KP, ARM, S-HK, and PLF. The first draft of the manuscript was written by RTM and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Phyllis L. Faust.

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Conflict of interest

ARM and Columbia University own shares in ARMGO Pharma, Inc. a biotech company developing RyR targeted therapeutics. All other authors declare no competing interests or conflicts.

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Supplementary Information

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401_2023_2602_MOESM1_ESM.tif

Supplemental Figure 1: RyR1 macromolecular complex of kinases, phosphatases, and accessory scaffold proteins. Cryo-EM structures of RyR1 (grey, PDB: 7M6A) with subunit calstabin-1 bound (yellow) and endoplasmic reticulum (ER) membrane (black), PP1/Spinophilin complex (blue/green PDB: 3EGG), PDE4 (purple, PDB:5K1I), mAKAP (cyan, AlphaFold), and PKA (orange, PDB:6MM5). Domain-domain interaction information among proteins is still missing. Spatial placement of proteins is just schematic. mAKAP = muscle A-kinase anchoring protein; PDE4 = phosphodiesterase-4; PKA = protein kinase A; PP1 = protein phosphatase 1; RyR1 = ryanodine receptor type 1 (TIF 25619 KB)

401_2023_2602_MOESM2_ESM.tif

Supplemental Figure 2: Additional Western blot correlations for RyR1 macromolecular scaffold proteins. Quantification of immunoblot from Figure 1a for a. Spinophillin/RyR1, b. PDE4/RyR1 and c. PKA/RyR1 showing no significant difference between ET and control (n = 8 for each), although the decrease in spinophillin protein is trending towards significance (p = 0.063) (TIF 5730 KB)

401_2023_2602_MOESM3_ESM.xlsx

Supplemental Table 1: Clinical demographic and pathological metrics for all patient samples. Clinical and pathological information for each patient cerebellum that was utilized in the biochemical analysis of the ‘leaky’ RyR channel complex via immunoprecipitation and for correlation with calstabin1-RyR1 binding assay. Purkinje cell (PC)/mm and torpedo/mm quantifications were analyzed from a LH&E (luxol fast blue-hematoxylin & eosin) stained slide of cerebellum. LH&E is a general histologic tissue stain that identifies cell bodies, nuclei and myelin sheaths. VGlut2 immunostain is used to quantify density of climbing fiber (CF) synapses on PC dendrites and % CFs in outer 20% of the cerebellar molecular layer (ML). Samples are indicated as being used in RyR1, RyR2 or both Western blot assays, and RyR1 binding assay (XLSX 15 KB)

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Martuscello, R.T., Chen, ML., Reiken, S. et al. Defective cerebellar ryanodine receptor type 1 and endoplasmic reticulum calcium ‘leak’ in tremor pathophysiology. Acta Neuropathol 146, 301–318 (2023). https://doi.org/10.1007/s00401-023-02602-z

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