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Aging and disease    2018, Vol. 9 Issue (2) : 208-219     DOI: 10.14336/AD.2017.0505
Orginal Article |
Glucocerebrosidase mRNA is Diminished in Brain of Lewy Body Diseases and Changes with Disease Progression in Blood
Perez-Roca Laia1, Adame-Castillo Cristina1, Campdelacreu Jaume2, Ispierto Lourdes3, Vilas Dolores3, Rene Ramon2, Alvarez Ramiro3, Gascon-Bayarri Jordi2, Serrano-Munoz Maria A.1, Ariza Aurelio1, Beyer Katrin1,*
1Department of Pathology, Hospital Universitari and Health Sciences Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Spain
2Department of Neurology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain
3Department of Neurology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain.
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Abstract  

Parkinson disease (PD) and dementia with Lewy bodies (DLB) are Lewy body diseases characterized by abnormal alpha-synuclein deposits and overlapping pathological features in the brain. Several studies have shown that glucocerebrosidase (GBA) deficiency is involved in the development of LB diseases. Here, we aimed to find out if this deficiency starts at the transcriptional level, also involves alternative splicing, and if GBA expression changes in brain are also detectable in blood of patients with LB diseases. The expression of three GBA transcript variants (GBAtv1, GBAtv2 and GBAtv5) was analyzed in samples from 20 DLB, 25 PD and 17 control brains and in blood of 20 DLB, 26 PD patients and 17 unaffected individuals. Relative mRNA expression was determined by real-time PCR. Expression changes were evaluated by the ΔΔCt method. In brain, specific expression profiles were identified in the temporal cortex of DLB and in the caudate nucleus of PD. In blood, significant GBA mRNA diminution was found in both DLB and PD patients. Early PD and early-onset DLB patients showed lowest GBA levels which were normal in PD patients with advanced disease and DLB patients who developed disease after 70 years of age. In conclusion, disease group specific GBA expression profiles were found in mostly affected areas of LBD. In blood, GBA expression was diminished in LB diseases, especially in patients with early onset DLB and in patients with early PD. Age of disease onset exerts an opposite effect on GBA expression in DLB and PD.

Keywords glucocerebrosidase deficiency      Parkinson’s disease      dementia with Lewy bodies      GBA mRNA expression      transcript variants     
Corresponding Authors: Beyer Katrin   
About author:

These authors contributed equally to this work.

Issue Date: 01 April 2018
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Perez-Roca Laia
Adame-Castillo Cristina
Campdelacreu Jaume
Ispierto Lourdes
Vilas Dolores
Rene Ramon
Alvarez Ramiro
Gascon-Bayarri Jordi
Serrano-Munoz Maria A.
Ariza Aurelio
Beyer Katrin
Cite this article:   
Perez-Roca Laia,Adame-Castillo Cristina,Campdelacreu Jaume, et al. Glucocerebrosidase mRNA is Diminished in Brain of Lewy Body Diseases and Changes with Disease Progression in Blood[J]. Aging and disease, 2018, 9(2): 208-219.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0505     OR     http://www.aginganddisease.org/EN/Y2018/V9/I2/208
DiseasenPMtime1 (range)ADstage2Br&Br3Death4 (range)M:F ratio5
pDLB689:30 (3:30-17:00)0-IIA-C74.6 (60-85)3:1
cDLB71210:30 (4:00-21:15)III-VIB-C79.0 (74-86)1.4:1
PD8127:00 (3:30-14:00)III-IV80.8 (68-93)1:1
PDD9137:10 (4:00-12:20)II-VIA-C78.7 (71-87)0.9:1
CTRL10178:40 (2:30-23:30)69.3 (55-81)1.4:1
Table 1  Clinico-neuropathological characteristics of Lewy body disease cases and controls.
Name and NCBI1Primer namePrimer sequence (5’ - 3’)Size2
GBA1tv1
NM_000157.3
GBA1tv1U*ATC ACA TGA CCC ATC CAC A214 bp3
GBA1tv1LACT CAA AGG CTT GGG ACA T
GBA1tv2
NM_001005741.2
GBA1tv2U2*TTC GCC GAC GTG GAT CCT CT236 bp
GBA1tv2L2ACC GAG CTG TAG CCG AAG CT
GBA1tv3
NM_001005742.2
GBA1tv3U*TTC GCC GAC GAG ACT CTG GA176 bp
GBA1tv3LACC TGA TGC CCA CGA CAC TG
GBA1tv4
NM_001171811.1
GBA1tv4U*TTC TCT TCG CCG ACG GTG CC169 bp
GBA1tv4LAGC TCC ATC CGT CGC CCA CT
GBA1tv5
NM_001171812.1
GBA1tv5U*ACG GGC ACA GGA ATC GGA TA173 bp
GBA1tv5LAAC TGC AGG GCT CGG TGA AT
b-act U2TCT ACA ATG AGC TGC GTG TG228 bp4
b-act L2GGA TAG CAA CGT ACA TGG CT
b-act U3AAC TGG GAC GAC ATG GAG AA178 bp5
b-act L3TAG ATG GGC ACA GTG TGG GT
GUS6-U1ATG TGG TTG GAG AGC TCA TT176 bp
GUS-L2TGT CTC TGC CGA GTG AAG AT
PBGD7_U1ACA CAC AGC CTA CTT TCC AAG183 bp
PBGD_L1TCA ATG TTG CCA CCA CAC TGT
Table 2  RNA primer sequences used for the amplification of GBA1 isoforms, beta-actin, GUS and PBGD.
Figure 1.  Schematic representation of the five GBA transcripts and location of forward primers. Grey boxes represent exons and the lines, introns. Narrow red rectangles at the end of some exons indicate sequences, chosen for designing isoform-specific primers.
Figure 2.  Relative GBA isoform expression in different brain areas. GBA expression in neural tissue estimated by appraising agarose gel electrophoretograms: tv, transcript variant; FC, frontal cortex; TC, temporal cortex; Ca, caudate nucleus; Put, putamen; NBM, Nucleus basalis of Meynert; Am, Amygdala; SN, Substantia nigra; Pt, pons; Cr, cerebellum. White fields correspond to lack of expression, light gray (1) to very slight expression, middle gray (2) to readily detectable expression, and dark gray (3) to high expression. The black fields represent very intense expression levels.
Figure 3.  Expression profiles of GBA1 isoforms in three brain areas of LBD after adjustment with controls. The included areas were temporal cortex (TC) and caudate nucleus (Ca) from the groups of pure dementia with Lewy bodies (pDLB), common dementia with Lewy bodies (cDLB), Parkinson′s disease without dementia (PDND) and Parkinson′s disease with dementia (PDD). The results are shown as relative expression changes obtained by the ΔΔCt method in comparison with normal controls and are represented in a logarithmic scale. Grey areas represent normal expression range. * Significant expression change below 0.5.
Figure 4.  GBA1tv1 expression in blood of DLB and PD patients in dependency on disease duration. GBA1tv1 expression was analyzed (A) in two groups and (B) for each patient individually. For (A), the results are shown as relative expression changes obtained by the ΔΔCt method in comparison with control individuals. * Significant expression change below 0.5. § Significant expression change between the disease duration subgroups. For (B) each point corresponds to the value of the expression change of each individual obtained by the ΔΔCt method, where ΔCt of patients was determined individually and ΔCt of control individuals was the mean value of the entire control group. Grey areas represent normal expression range.
DLB
Disease onset<65 years>65 yearsP1
n614
age at onset (range)61.4 (59-65)68.5 (66-74)n.p.2
age (range)67.6 (63-71)73.8 (69-80)n.p.
duration (range)6.2 (2-10)4.9 (2-10)0.135
male: female ratio1: 0.331: 0.40.765
Disease duration since onset<6 years>6 years
n137
age at onset (range)67.1 (59-74)63.5 (60-67)0.238
age (range)70.8 (63-80)72.8 (70-77)0.302
male:female ratio1: 0.51: 0.250.097
PD
Disease onset<65 years>65 years
n1214
age at onset (range)62.2 (60-64)70.0 (68-73)n.p.
age (range)69.0 (61-75)72.5 (68-75)n.p.
duration (range)6.8 (1-14)2.5 (0-6)0.015
male: female ratio1: 0.81:010.827
Disease duration since onset<6 years>6 years
n1511
age at onset (range)66.9 (60-73)61.7 (60-64)0.105
age (range)69.6 (61-75)72.3 (68-75)0.376
male: female ratio1: 0.91: 0.91
Table 3  Clinical characteristics of DLB and PD patients in the disease onset and duration groups.
Figure 5.  GBA1tv1 expression in blood of DLB and PD patients in dependency on the age of disease onset. GBA1tv1 expression was analyzed (A) in two groups and (B) for each patient individually. For (A), the results are shown as relative expression changes obtained by the ΔΔCt method in comparison with control individuals. *Significant expression change below 0.5. #Significant expression change between the age-at-onset dependent subgroups. For (B) each point corresponds to the value of the expression change of each individual obtained by the ΔΔCt method, where ΔCt of patients was determined individually and ΔCt of control individuals was the mean value of the entire control group. Grey areas represent normal expression range.
[1] Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998). Alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA, 95:6469-73.
[2] Braak H, Braak E (1997). Diagnostic criteria for neuropathological assessment of Alzheimer’s disease. Neurobiol Aging, 18:S85-8.
[3] Jellinger KA (2009). A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta, 1792:730-40.
[4] Ferman TJ, Boeve BF (2007). Dementia with Lewy bodies. Neurol Clin, 25:741-60.
[5] Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sørensen P (2003). Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol, 60:387-92.
[6] Beutler E, Grabowski GA (2001). Glucosylceramide lipidosis-Gaucher disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited diseases. 8th edition, 3635-68.
[7] Li Y, Li P, Liang H, Zhao Z, Hashimoto M, Wei J (2015). Gaucher-Associated Parkinsonism. Cell Mol Neurobiol, 35:755-61.
[8] Goker-Alpan O, Giasson BI, Eblan MJ, Nguyen J, Hurtig HI, Lee VM, et al. (2006). Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology, 67:908-10.
[9] Goker-Alpan O, Schiffmann R, LaMarca ME, Nussbaum RL, McInerney-Leo A, Sidransky E (2004). Parkinsonism among Gaucher disease carriers. J Med Genet, 41:937-40.
[10] Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, et al. (2008). Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol, 65:379-82.
[11] Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, et al. (2013). A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol, 70:727-35.
[12] Murphy KE, Gysbers AM, Abbott SK, Tayebi N, Kim WS, Sidransky E, et al. (2014). Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson’s disease. Brain, 137:834-48.
[13] Pitcher TL, Melzer TR, Macaskill MR, Graham CF, Livingston L, Keenan RJ, et al. (2012). Reduced striatal volumes in Parkinson’s disease: a magnetic resonance imaging study. Transl Neurodegener, 1:17.
[14] Alcalay RN, Levy OA, Waters CC, Fahn S, Ford B, Kuo SH, et al. (2015). Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain, 138:2648-58.
[15] Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, et al. (2011). Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell, 146:37-52.
[16] Harries LW, Hernandez D, Henley W, Wood AR, Holly AC, Bradley-Smith RM, et al. (2011). Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell, 10:868-78.
[17] Zhang J, Manley JL (2013). Misregulation of pre-mRNA alternative splicing in cancer. Cancer Discov, 3:1228-37.
[18] Beyer K, Domingo-Sàbat M, Humbert J, Carrato C, Ferrer I, Ariza A (2008). Differential expression of alpha-synuclein, parkin, and synphilin-1 isoforms in Lewy body disease. Neurogenetics, 9:163-72.
[19] Beyer K, Munoz-Marmol AM, Sanz C, Marginet-Flinch R, Ferrer I, Ariza A (2012). New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases. Neurogenetics, 13:61-72.
[20] Beyer K, Domingo-Sàbat M, Santos C, Tolosa E, Ferrer I, Ariza A (2010). The decrease of β-synuclein in cortical brain areas defines a molecular subgroup of dementia with Lewy bodies. Brain, 133:3724-33.
[21] McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, et al. (2005). Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology, 65:1863-72.
[22] Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992). Accuracy of clinical diagnosis of idiopathic Parkinson’s disease. A clinico-pathological study of 100 cases. JNNP, 55:181-4. [23]
[23] Winfield SL, Tayebi N, Martin BM, Ginns EI, Sidransky E (1997). Identification of three additional genes contiguous to the glucocerebrosidase locus on chromosome 1q21: implications for Gaucher disease. Genome Res, 7:1020-6.
[24] Durrenberger PF, Fernando S, Kashefi SN, Ferrer I, Hauw JJ, Seilhean D, et al (2010). Effects of antemortem and postmortem variables on human brain mRNA quality: a BrainNet Europe study. J Neuropathol Exp Neurol, 69:70-81.
[25] Popova T, Mennerich D, Weith A, Quast K (2008). Effect of RNA quality on transcript intensity levels in microarray analysis of human post-mortem brain tissues. BMC Genomics, 9:91.
[26] Barrachina M, Castaño E, Ferrer I (2006). TaqMan PCR assay in the control of RNA normalization in human post-mortem brain tissue. Neurochem Int, 49:276-84.
[27] Fuchs J, Tichopad A, Golub Y, Munz M, Schweitzer KJ, Wolf B, et al. (2008). Genetic variability in the SNCA gene influences alpha-synuclein levels in the blood and brain. FASEB J, 22:1327-34.
[28] Schefe JH, Lehmann KE, Buschmann IR, Unger T, Funke-Kaiser H (2006). Quantitative real-time RT-PCR data analysis: current concepts and the novel “gene expression’s C T difference” formula. J Mol Med, 84:901-10.
[29] Schmittgen TD, Livak KJ (2008). Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc, 3:1101-8.
[30] Rutledge RG, Côté C (2003). Mathematics of quantitative kinetic PCR and the application of standard curves. Nucleic Acids Res, 31:e93.
[31] Yao P, Lin P, Gokoolparsadh A, Assareh A, Thang MW, Voineagu I (2015). Coexpression networks identify brain region-specific enhancer RNAs in the human brain. Nat Neurosci, 18:1168-74.
[32] Bagot RC, Cates HM, Purushothaman I, Lorsch ZS, Walker DM, Wang J, et al. (2016). Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility. Neuron, 90:969-83.
[33] Mak E, Su L, Williams GB, Watson R, Firbank M, Blamire A, et al. (2015). Progressive cortical thinning and subcortical atrophy in dementia with Lewy bodies and Alzheimer’s disease. Neurobiol Aging, 36:1743-50.
[34] O’Brien JT, Colloby S, Fenwick J, Williams ED, Firbank M, Burn D, et al. (2004). Dopamine transporter loss visualized with FP-CIT SPECT in the differential diagnosis of dementia with Lewy bodies. Arch Neurol, 61:919-25.
[35] Niethammer M, Tang CC, Ma Y, Mattis PJ, Ko JH, Dhawan V, et al. (2013). Parkinson’s disease cognitive network correlates with caudate dopamine. Neuroimage, 78:204-9.
[36] Gegg ME, Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW, et al. (2012). Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol, 72:455-63.
[37] Kurzawa-Akanbi M, Hanson PS, Blain PG, Lett DJ, McKeith IG, Chinnery PF, et al (2012). Glucocerebrosidase mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease. J Neurochem, 123:298-309.
[38] Rocha EM, Smith GA, Park E, Cao H, Brown E, Hallett P, et al (2015). Progressive decline of glucocerebrosidase in aging and Parkinson’s disease. Ann Clin Transl Neurol, 2:433-8.
[39] Zarow C, Lyness SA, Mortimer JA, Chui HC (2003). Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol, 60:337-41.
[40] Windisch M, Hutter-Paier B, Rockenstein E, Hashimoto M, Mallory M, Masliah E (2002). Development of a new treatment for Alzheimer’s disease and Parkinson’s disease using anti-aggregatory beta-synuclein-derived peptides. J Mol Neurosci, 19:63-9.
[41] Wei J, Fujita M, Nakai M, Waragai M, Sekigawa A, Sugama S, et al (2009). Protective role of endogenous gangliosides for lysosomal pathology in a cellular model of synucleinopathies. Am J Pathol, 174:1891-909.
[42] Fujita M, Sugama S, Sekiyama K, Sekigawa A, Tsukui T, Nakai M, et al (2010). A β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain. Nat Commun, 1:110.
[43] Blanz J, Groth J, Zachos C, Wehling C, Saftig P, Schwake M (2010). Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP2) reveal the nature of binding to its ligand beta-glucocerebrosidase. Hum Mol Genet, 19:563-72.
[44] Chikina MD, Gerald CP, Li X, Ge Y, Pincas H, Nair VD, et al. (2015). Low-variance RNAs identify Parkinson’s disease molecular signature in blood. Mov Disord, 30:813-21.
[45] Locascio JJ, Eberly S, Liao Z, Liu G, Hoesing AN, Duong K, Trisini-Lipsanopoulos A, et al. (2015). Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson’s disease. Brain, 138:2659-71.
[46] Santiago JA, Potashkin JA (2015). Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson’s Disease Patients. PLoS One, 10:e0142582.
[47] Santiago JA, Potashkin JA (2015). Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease. Proc Natl Acad Sci U S A, 112:2257-62.
[48] Van Rooden SM, Heiser WJ, Kok JN, Verbaan D, van Hilten JJ, Marinus J (2010). The identification of Parkinson’s disease subtypes using cluster analysis: a systematic review. Mov Disord, 25:969-78.
[49] Schneider SA, Obeso JA (2015). Clinical and pathological features of Parkinson’s disease. Curr. Top Behav Neurosci, 22:205-20.
[50] Fujishiro H, Iseki E, Nakamura S, Kasanuki K, Chiba Y, Ota K, et al. (2013). Dementia with Lewy bodies: early diagnostic challenges. Psychogeriatrics, 13:128-38.
[51] Mayo MC, Bordelon Y (2014). Dementia with Lewy bodies. Semin Neurol, 34:182-8.
[52] McKeith I, Taylor JP, Thomas A, Donaghy P, Kane J (2016). Revisiting DLB Diagnosis: A Consideration of Prodromal DLB and of the Diagnostic Overlap With Alzheimer Disease. J. Geriatr Psychiatry Neurol, 29:249-53.
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