myelin proteolipid protein

Summary

Summary: A myelin protein that is the major component of the organic solvent extractable lipoprotein complexes of whole brain. It has been the subject of much study because of its unusual physical properties. It remains soluble in chloroform even after essentially all of its bound lipids have been removed. (From Siegel et al., Basic Neurochemistry, 4th ed, p122)

Top Publications

  1. Bell J, Divekar R, Ellis J, Cascio J, Haymaker C, Jain R, et al. In trans T cell tolerance diminishes autoantibody responses and exacerbates experimental allergic encephalomyelitis. J Immunol. 2008;180:1508-16 pubmed
    ..Thus, in trans T cell tolerance, which should be operative in polymorphic systems, can aggravate rather than ameliorate autoimmunity. This phenomenon possibly takes place through interference with protective humoral immunity. ..
  2. Stefanova N, Kaufmann W, Humpel C, Poewe W, Wenning G. Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human ?-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. Acta Neuropathol. 2012;124:51-65 pubmed publisher
    ..In summary, we provide new evidence supporting a primary role of proteolytic failure and suggesting a neurodegenerative pathomechanism related to disturbed oligodendroglial/myelin trophic support in the pathogenesis of MSA. ..
  3. Aboul Enein F, Weiser P, Hoftberger R, Lassmann H, Bradl M. Transient axonal injury in the absence of demyelination: a correlate of clinical disease in acute experimental autoimmune encephalomyelitis. Acta Neuropathol. 2006;111:539-47 pubmed
    ..Our studies suggest that nitric oxide and its metabolites contribute to axonal pathology and possibly also to subsequent neurological dysfunction in EAE. ..
  4. Lee E, Moon H, Park Y, Garbern J, Hobson G. A case of complicated spastic paraplegia 2 due to a point mutation in the proteolipid protein 1 gene. J Neurol Sci. 2004;224:83-7 pubmed
    ..The distinct severity difference between the Pro215Leu and Pro215Ala substitutions suggests that this region of the protein is very sensitive to subtle structural changes and likely plays a critical role in PLP1 function. ..
  5. Edgar J, McCulloch M, Montague P, Brown A, Thilemann S, Pratola L, et al. Demyelination and axonal preservation in a transgenic mouse model of Pelizaeus-Merzbacher disease. EMBO Mol Med. 2010;2:42-50 pubmed publisher
    ..Our results suggest that neuroinflammation and/or oligodendrocyte dysfunction are more deleterious for axonal health than demyelination per se, at least in the short term. ..
  6. Tigno Aranjuez J, Jaini R, Tuohy V, Lehmann P, Tary Lehmann M. Encephalitogenicity of complete Freund's adjuvant relative to CpG is linked to induction of Th17 cells. J Immunol. 2009;183:5654-61 pubmed publisher
    ..The data show that immunizations using the autoantigen in CpG 1826/IFA result in very low frequencies of Ag-specific IL-17 cells, suggesting a lower risk of Th17-mediated pathology when using this adjuvant. ..
  7. Miller M, Kangas C, Macklin W. Neuronal expression of the proteolipid protein gene in the medulla of the mouse. J Neurosci Res. 2009;87:2842-53 pubmed publisher
    ..Thus, Plp expression in the mouse caudal medulla was found to be developmentally regulated and restricted to specific groups of neurons. ..
  8. Tanaka H, Ma J, Tanaka K, Takao K, Komada M, Tanda K, et al. Mice with altered myelin proteolipid protein gene expression display cognitive deficits accompanied by abnormal neuron-glia interactions and decreased conduction velocities. J Neurosci. 2009;29:8363-71 pubmed publisher
    ..To address these questions, we analyzed a transgenic mouse line harboring extra copies of the myelin proteolipid protein 1 (plp1) gene (plp1(tg/-) mice) at 2 months of age...
  9. Koizume S, Takizawa S, Fujita K, Aida N, Yamashita S, Miyagi Y, et al. Aberrant trafficking of a proteolipid protein in a mild Pelizaeus-Merzbacher disease. Neuroscience. 2006;141:1861-9 pubmed
    ..This mutant PLP, with its distribution outside the ER and a very mild phenotype, supports the idea that accumulation of misfolded mutant protein in the ER causes the severe phenotype of PMD. ..

More Information

Publications62

  1. Zhu H, Zhao L, Wang E, Dimova N, Liu G, Feng Y, et al. The QKI-PLP pathway controls SIRT2 abundance in CNS myelin. Glia. 2012;60:69-82 pubmed publisher
    ..Collectively, our results indicate that the abundance of SIRT2 in myelin is dependent on PLP, but not DM20. ..
  2. Gudz T, Komuro H, Macklin W. Glutamate stimulates oligodendrocyte progenitor migration mediated via an alphav integrin/myelin proteolipid protein complex. J Neurosci. 2006;26:2458-66 pubmed
    ..A protein complex containing the myelin proteolipid protein (PLP) and alphav integrin modulated the AMPA-stimulated migration, and stimulation of OPC AMPA receptors ..
  3. Clark K, Sakowski L, Sperle K, Banser L, Landel C, Bessert D, et al. Gait abnormalities and progressive myelin degeneration in a new murine model of Pelizaeus-Merzbacher disease with tandem genomic duplication. J Neurosci. 2013;33:11788-99 pubmed publisher
    ..Our results show that a single duplication of the Plp1 gene leads to a phenotype similar to the pattern seen in human PMD patients with duplications. ..
  4. Ng D, Deber C. Modulation of the oligomerization of myelin proteolipid protein by transmembrane helix interaction motifs. Biochemistry. 2010;49:6896-902 pubmed publisher
    ..The overall results suggest that TM segments in misfolded PLP monomers that expose and/or create surface-exposed helix-helix interaction sites that are normally masked may have consequences for disease. ..
  5. Shimojima K, Mano T, Kashiwagi M, Tanabe T, Sugawara M, Okamoto N, et al. Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication-duplication in chromosomal segments including the PLP1 region. Eur J Med Genet. 2012;55:400-3 pubmed publisher
    ..This is the first report of a patient with PLP1 triplication caused by a DUP-TRP/INV-DUP structure. This study adds additional evidence about the consequences of PLP1 triplication. ..
  6. Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics. 2005;6:1-16 pubmed
    ..Here, I review the previous and current knowledge of the molecular pathogenesis of PMD/SPG2 and delineate future directions for PMD/SPG2 studies. ..
  7. Wolf N, Sistermans E, Cundall M, Hobson G, Davis Williams A, Palmer R, et al. Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain. 2005;128:743-51 pubmed
    ..It highlights the significance of PLP1 dosage in CNS myelinogenesis as well as the importance of accurate determination of PLP1 gene copy number in the diagnosis of PMD and carrier detection. ..
  8. Hobson G, Huang Z, Sperle K, Sistermans E, Rogan P, Garbern J, et al. Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes. Hum Mutat. 2006;27:69-77 pubmed
  9. Southwood C, Olson K, Wu C, Gow A. Novel alternatively spliced endoplasmic reticulum retention signal in the cytoplasmic loop of Proteolipid Protein-1. J Neurosci Res. 2007;85:471-8 pubmed
    ..Accordingly, the function of this novel heptapeptide has a significant impact on pathogenesis and provides new insight into the functions of the two splice isoforms encoded by the PLP1 gene, PLP1 and DM-20. ..
  10. Weigel I, Schulze G, Pischetsrieder M. Immunochemical detection of tissue from the central nervous system via myelin proteolipid protein: adaptation for food inspection and development of recombinant bivalent Fab mini-antibodies. J Agric Food Chem. 2010;58:6587-93 pubmed publisher
    ..A Western blot assay for the specific CNS tissue marker myelin proteolipid protein (PLP) was optimized with considerably reduced analysis time, solvent consumption, and detection limit (0...
  11. Sarret C, Combes P, Micheau P, Gelot A, Boespflug Tanguy O, Vaurs Barriere C. Novel neuronal proteolipid protein isoforms encoded by the human myelin proteolipid protein 1 gene. Neuroscience. 2010;166:522-38 pubmed publisher
    The human myelin proteolipid protein 1 gene (hPLP1), which encodes the major structural myelin proteins of the central nervous system (CNS), is classically described as expressed in the oligodendrocytes, the CNS myelinating cells...
  12. Grossi S, Regis S, Biancheri R, Mort M, Lualdi S, Bertini E, et al. Molecular genetic analysis of the PLP1 gene in 38 families with PLP1-related disorders: identification and functional characterization of 11 novel PLP1 mutations. Orphanet J Rare Dis. 2011;6:40 pubmed publisher
    ..paraplegia type 2 is due to the extensive allelic heterogeneity in the X-linked PLP1 gene encoding myelin proteolipid protein (PLP)...
  13. Lee J, Carvalho C, Lupski J. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell. 2007;131:1235-47 pubmed
    ..We propose that complex duplication and deletion rearrangements associated with PMD, and potentially other nonrecurrent rearrangements, may be explained by this replication-based mechanism. ..
  14. Wang E, Dimova N, Cambi F. PLP/DM20 ratio is regulated by hnRNPH and F and a novel G-rich enhancer in oligodendrocytes. Nucleic Acids Res. 2007;35:4164-78 pubmed
    ..We conclude that developmental changes in hnRNPH/F associated with OLs differentiation synergistically regulate PLP alternative splicing and a G-rich enhancer participates in the regulation. ..
  15. Hofstetter H, Toyka K, Tary Lehmann M, Lehmann P. Kinetics and organ distribution of IL-17-producing CD4 cells in proteolipid protein 139-151 peptide-induced experimental autoimmune encephalomyelitis of SJL mice. J Immunol. 2007;178:1372-8 pubmed
    ..The selective enrichment of IL-17-producing CD4 cells in the CNS is suggestive of the pathogenic role of an independent (non-Th1) IL-17-producing proinflammatory effector T cell class in EAE. ..
  16. Combes P, Bonnet Dupeyron M, Gauthier Barichard F, Schiffmann R, Bertini E, Rodriguez D, et al. PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: Identification of one partial triplication and two partial deletions of PLP1. Neurogenetics. 2006;7:31-7 pubmed
  17. Regis S, Grossi S, Corsolini F, Biancheri R, Filocamo M. PLP1 gene duplication causes overexpression and alteration of the PLP/DM20 splicing balance in fibroblasts from Pelizaeus-Merzbacher disease patients. Biochim Biophys Acta. 2009;1792:548-54 pubmed publisher
    ..Therefore, PLP1 gene duplication seems to result both in overexpression and in a shift of the PLP/DM20 splicing balance in direction of the PLP isoform. ..
  18. Kroner A, Schwab N, Ip C, Leder C, Nave K, Maurer M, et al. PD-1 regulates neural damage in oligodendroglia-induced inflammation. PLoS ONE. 2009;4:e4405 pubmed publisher
    ..Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system. ..
  19. Ip C, Kohl B, Kleinschnitz C, Reuss B, Nave K, Kroner A, et al. Origin of CD11b+ macrophage-like cells in the CNS of PLP-overexpressing mice: low influx of haematogenous macrophages and unchanged blood-brain-barrier in the optic nerve. Mol Cell Neurosci. 2008;38:489-94 pubmed publisher
    ..Our study demonstrates an intrinsic origin of CD11b+ cells in the presence of an unchanged blood-brain-barrier in a CNS myelin mutant. ..
  20. Greenfield E, Reddy J, Lees A, Dyer C, Koul O, Nguyen K, et al. Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species. J Neurosci Res. 2006;83:415-31 pubmed
    b>Myelin proteolipid protein (PLP), the major protein of mammalian CNS myelin, is a member of the proteolipid gene family (pgf)...
  21. Guo F, Maeda Y, Ma J, Xu J, Horiuchi M, Miers L, et al. Pyramidal neurons are generated from oligodendroglial progenitor cells in adult piriform cortex. J Neurosci. 2010;30:12036-49 pubmed publisher
    ..Our data suggest that NG2(+)/PDGFR?(+) proteolipid protein promoter-expressing progenitors generate pyramidal glutamatergic neurons within normal adult piriform cortex. ..
  22. Schneider A, Länder H, Schulz G, Wolburg H, Nave K, Schulz J, et al. Palmitoylation is a sorting determinant for transport to the myelin membrane. J Cell Sci. 2005;118:2415-23 pubmed
    ..Thus, we conclude that palmitoylation is a sorting determinant for transport to the myelin membrane. ..
  23. Winterstein C, Trotter J, Krämer Albers E. Distinct endocytic recycling of myelin proteins promotes oligodendroglial membrane remodeling. J Cell Sci. 2008;121:834-42 pubmed publisher
    ..Our results suggest that endocytic sorting and recycling of myelin proteins may assist plasma membrane remodeling, which is necessary for the morphogenesis of myelin subdomains. ..
  24. Schweitzer J, Becker T, Schachner M, Nave K, Werner H. Evolution of myelin proteolipid proteins: gene duplication in teleosts and expression pattern divergence. Mol Cell Neurosci. 2006;31:161-77 pubmed
    ..Comparing protein sequences and gene structures from birds, teleosts, one urochordate species, and four invertebrates, we have reconstructed major steps in the evolution of proteolipids. ..
  25. Ercolini A, Ludovic Croxford J, DeGutes M, Miller S. Cross-reactivity between peptide mimics of the immunodominant myelin proteolipid protein epitope PLP139-151: comparison of peptide priming in CFA vs. viral delivery. J Neuroimmunol. 2007;186:5-18 pubmed
    ..The pattern of in vitro reactivity and ability to induce CNS disease differs between peptide priming and virus infection...
  26. Warshawsky I, Chernova O, Hübner C, Stindl R, Henneke M, Gal A, et al. Multiplex ligation-dependent probe amplification for rapid detection of proteolipid protein 1 gene duplications and deletions in affected males and carrier females with Pelizaeus-Merzbacher disease. Clin Chem. 2006;52:1267-75 pubmed
    ..3%-9.8%. MLPA is a rapid and reliable method to determine PLP1 gene copies. Samples with partial PLP1 gene dosage alterations require confirmation with a non-MLPA method. ..
  27. Dhaunchak A, Colman D, Nave K. Misalignment of PLP/DM20 transmembrane domains determines protein misfolding in Pelizaeus-Merzbacher disease. J Neurosci. 2011;31:14961-71 pubmed publisher
    ..We conclude that an important determinant in the quality control of polytopic membrane proteins is the free alignment of their TM domains. ..
  28. Rosenbluth J, Nave K, Mierzwa A, Schiff R. Subtle myelin defects in PLP-null mice. Glia. 2006;54:172-82 pubmed
  29. Sima A, Pierson C, Woltjer R, Hobson G, Golden J, Kupsky W, et al. Neuronal loss in Pelizaeus-Merzbacher disease differs in various mutations of the proteolipid protein 1. Acta Neuropathol. 2009;118:531-9 pubmed publisher
    ..While the precise pathogenetic mechanisms are not known, these observations suggest that defective glial functions contribute to neuronal pathology. ..
  30. Woodward K, Cundall M, Sperle K, Sistermans E, Ross M, Howell G, et al. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am J Hum Genet. 2005;77:966-87 pubmed
  31. Warshawsky I, Rudick R, Staugaitis S, Natowicz M. Primary progressive multiple sclerosis as a phenotype of a PLP1 gene mutation. Ann Neurol. 2005;58:470-3 pubmed
    ..This case goes against dogma that mothers of severely affected sons are asymptomatic as adults and expands the differential diagnosis of primary progressive multiple sclerosis to include proteolipid protein 1 gene mutations. ..
  32. Garbern J. Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis. Cell Mol Life Sci. 2007;64:50-65 pubmed
    ..and the allelic spastic paraplegia type 2 (SPG2) arise from mutations in the X-linked gene encoding myelin proteolipid protein (PLP)...
  33. Swanton E, Holland A, High S, Woodman P. Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2005;102:4342-7 pubmed
    ..Based on these findings, we propose that the premature oligomerization of PLP in the ER of oligodendrocytes contributes to the pathology of PMD. ..
  34. Hurst S, Garbern J, Trepanier A, Gow A. Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease. Genet Med. 2006;8:371-8 pubmed
    ..Effective genetic counseling of Pelizaeus-Merzbacher disease and spastic paraplegia carrier females must include an assessment of disease severity in affected male relatives. ..
  35. Edgar J, McLaughlin M, Werner H, McCulloch M, Barrie J, Brown A, et al. Early ultrastructural defects of axons and axon-glia junctions in mice lacking expression of Cnp1. Glia. 2009;57:1815-24 pubmed publisher
    ..These observations support a model in which the trophic functions of oligodendrocytes serve to offset the physical shielding of axons by myelin membranes. ..
  36. Grundtner R, Dornmair K, Dahm R, Flügel A, Kawakami N, Zeitelhofer M, et al. Transition from enhanced T cell infiltration to inflammation in the myelin-degenerative central nervous system. Neurobiol Dis. 2007;28:261-75 pubmed
    ..The activation of the tethered cells may trigger the formation of inflammatory foci and could pave the way for inflammation in degenerative CNS disease. ..
  37. Trajkovic K, Dhaunchak A, Goncalves J, Wenzel D, Schneider A, Bunt G, et al. Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites. J Cell Biol. 2006;172:937-48 pubmed
    ..The release of myelin membrane from LEs/Ls by neuronal signals may represent a mechanism to control myelin membrane growth. ..
  38. Ip C, Kroner A, Bendszus M, Leder C, Kobsar I, Fischer S, et al. Immune cells contribute to myelin degeneration and axonopathic changes in mice overexpressing proteolipid protein in oligodendrocytes. J Neurosci. 2006;26:8206-16 pubmed
    ..These findings provide strong evidence that a primary glial damage can cause secondary immune reactions of pathological significance as it has been suggested for some forms of multiple sclerosis and other leukodystrophies. ..
  39. Regis S, Grossi S, Lualdi S, Biancheri R, Filocamo M. Diagnosis of Pelizaeus-Merzbacher disease: detection of proteolipid protein gene copy number by real-time PCR. Neurogenetics. 2005;6:73-8 pubmed
    ..The method is suitable for the identification of affected male patients and female carriers. Specific ranges are widely spaced, ensuring a correct assignment of the PLP1 gene copy number. ..
  40. Wang E, Huang Z, Hobson G, Dimova N, Sperle K, McCullough A, et al. PLP1 alternative splicing in differentiating oligodendrocytes: characterization of an exonic splicing enhancer. J Cell Biochem. 2006;97:999-1016 pubmed
    ..We conclude that an ESE in exon3B regulates PLP 5' donor site selection and that ASF/SF2 protein participates in the regulation of PLP alternative splicing in oligodendrocytes. ..
  41. Lee J, Cheung S, Ward P, Inoue K, Lupski J. Prenatal diagnosis of PLP1 copy number by array comparative genomic hybridization. Prenat Diagn. 2005;25:1188-91 pubmed
    ..aCGH is a reliable alternative method for detection of PLP1 copy number for prenatal diagnosis of Pelizaeus-Merzbacher disease. ..
  42. Krämer Albers E, Gehrig Burger K, Thiele C, Trotter J, Nave K. Perturbed interactions of mutant proteolipid protein/DM20 with cholesterol and lipid rafts in oligodendroglia: implications for dysmyelination in spastic paraplegia. J Neurosci. 2006;26:11743-52 pubmed
    ..Whereas UPR-induced cell death governs the PMD phenotype of the msd mutation, we propose that impaired cholesterol and lipid raft interaction of the rsh protein may contribute to the dysmyelination observed in SPG-2. ..
  43. Muncke N, Wogatzky B, Breuning M, Sistermans E, Endris V, Ross M, et al. Position effect on PLP1 may cause a subset of Pelizaeus-Merzbacher disease symptoms. J Med Genet. 2004;41:e121 pubmed
  44. Ochoa Reparaz J, Mielcarz D, Ditrio L, Burroughs A, Foureau D, Haque Begum S, et al. Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol. 2009;183:6041-50 pubmed publisher
    ..This approach may offer a new therapeutic paradigm in the treatment of multiple sclerosis and perhaps other autoimmune conditions. ..
  45. Regis S, Biancheri R, Bertini E, Burlina A, Lualdi S, Bianco M, et al. Genotype-phenotype correlation in five Pelizaeus-Merzbacher disease patients with PLP1 gene duplications. Clin Genet. 2008;73:279-87 pubmed publisher
    ..Interestingly enough, each duplication had one of the two breakpoints in or near to low copy repeats (LCRs), supporting recent evidence concerning a possible role of LCRs in the generation of the duplications in PMD. ..
  46. Wight P, Duchala C, Shick H, Gudz T, Macklin W. Expression of a myelin proteolipid protein (Plp)-lacZ transgene is reduced in both the CNS and PNS of Plp(jp) mice. Neurochem Res. 2007;32:343-51 pubmed
    ..It results from a point mutation in the acceptor splice site of myelin proteolipid protein (Plp) exon 5, producing transcripts that are missing exon 5, with a concomitant shift in the downstream ..
  47. Feldmann A, Amphornrat J, Sch nherr M, Winterstein C, M bius W, Ruhwedel T, et al. Transport of the major myelin proteolipid protein is directed by VAMP3 and VAMP7. J Neurosci. 2011;31:5659-72 pubmed publisher
    ..VAMP3 and VAMP7 colocalize with the major myelin proteolipid protein (PLP) in recycling endosomes and late endosomes/lysosomes, respectively...
  48. Woodward K. The molecular and cellular defects underlying Pelizaeus-Merzbacher disease. Expert Rev Mol Med. 2008;10:e14 pubmed publisher
    ..This article reviews the genetics of PMD and summarises the current knowledge of causative molecular and cellular mechanisms. ..
  49. Bachstetter A, Webster S, Van Eldik L, Cambi F. Clinically relevant intronic splicing enhancer mutation in myelin proteolipid protein leads to progressive microglia and astrocyte activation in white and gray matter regions of the brain. J Neuroinflammation. 2013;10:146 pubmed publisher
  50. Rosenbluth J, Schiff R, Lam P. Effects of osmolality on PLP-null myelin structure: implications re axon damage. Brain Res. 2009;1253:191-7 pubmed publisher
    ..Mechanisms by which impaired adhesiveness of PLP-null myelin lamellae and fluctuations in osmolality in vivo might underlie slowing of conduction and axon damage are discussed. ..
  51. Wang E, Dimova N, Sperle K, Huang Z, Lock L, McCulloch M, et al. Deletion of a splicing enhancer disrupts PLP1/DM20 ratio and myelin stability. Exp Neurol. 2008;214:322-30 pubmed publisher
    ..This knockin mouse represents a useful model to investigate the mechanisms of disease in human disorders in which PLP1 expression is reduced. ..
  52. Tuason M, Rastikerdar A, Kuhlmann T, Goujet Zalc C, Zalc B, Dib S, et al. Separate proteolipid protein/DM20 enhancers serve different lineages and stages of development. J Neurosci. 2008;28:6895-903 pubmed publisher
    ..The transgenic lines derived here also provide effective markers for multiple stages of glial and neuronal lineage progression. ..
  53. Greer J, Csurhes P, Muller D, Pender M. Correlation of blood T cell and antibody reactivity to myelin proteins with HLA type and lesion localization in multiple sclerosis. J Immunol. 2008;180:6402-10 pubmed
    ..In these 40 patients, the most robust correlation was between CD4(+) T cell reactivity to myelin proteolipid protein residues 184-209 (PLP(184-209)) and development of lesions in the brainstem and cerebellum...