Skip to main content
  • Research article
  • Open access
  • Published:

Association between NMD3 and symptoms of Parkinson’s disease in Chinese patients

Abstract

Background

Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder that is characterized by motor symptoms such as tremor, rigidity, slowness of movement and problems with gait. Large-scale meta-analyses of genome-wide association studies (GWAS) have identified few susceptibility loci in patients with sporadic PD. The aim of this study was to investigate the association between NMD3 single nucleotide polymorphism (SNP) and symptoms in PD patients in South China.

Methods

A total of 217 PD patients were recruited in this study and genotyped by using the SNaPshot technique and the polymerase chain reaction. All subjects were evaluated by the Mini-Mental State Examination (MMSE), Beijing version Montreal Cognitive Assessment (MoCA), Sniffin’ Sticks 16 (SS-16), Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, 39-item Parkinson’s Disease Questionnaire (PDQ-39) and MDS Unified PD Rating Scale (MDS-UPDRS).

Results

NMD3 rs34016896 (C > T) carriers have worse cognitive function than wild types (MMSE: p = 0.042, NMD3 wild type: 27.44 ± 2.89, NMD3 carriers: 26.31 ± 3.79; MoCA: p = 0.005, NMD3 wild type: 23.15 ± 4.20, NMD3 carriers: 20.75 ± 6.68).

Conclusions

The recessive and overdominant model of NMD3 rs34016896 was associated with cognitive impairment in PD patients.

Peer Review reports

Background

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, affecting approximately 1.7% of people over the age of 65, and the annual incidence ranges from 1.5 to 8.7/100,000 in the People’s Republic of China [1]. The pathological features of PD are the abnormal aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra [2]. Both acquired and inherited risk factors have been implicated in the death of dopaminergic neurons [3]. Genetic factors play a crucial role in the pathogenesis of sporadic PD. Genome-wide association studies (GWAS) have identified several susceptibility loci for PD [4,5,6]. Genes such as LRRK2, SNC A, etc. have been associated with the pathogenesis of PD [7, 8]. Marie Y. Davis reported that GBA variants predicted a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD [9].

Recently, variants at NMD3 were found to be related to substantia nigra neuronal loss and PD susceptibility [10, 11]. The minor allele frequency of NMD3 rs34016896 was 0.41 in the Chinese PD population and 0.45 in the Chinese healthy population [11]. NMD3 encodes a ribosome-binding protein. Nmd3 is a structural mimic of eIF5A and activates the cpGTPase Lsg1 during 60S ribosome biogenesis [12]. Associations of NMD3 rs34016896 with clinical pathological phenotypes have been discovered. JM Shulman and colleagues found that NMD3 rs34016896 was related to the severity of nigral neuronal loss and not to Lewy bodies [13]. However, the function of NMD3 in PD is unknown. In addition, it is necessary to investigate the association between NMD3 and clinical symptoms of PD, which could indicate the pathogenesis of PD.

In this study, we attempted to discover the clinical hallmarks of NMD3 rs34016896 (C > T) in southern Chinese PD patients.

Methods

Study population

PD patients were recruited from the outpatients clinic of Ren Ji Hospital (South Campus) and diagnosed by movement disorder specialists based on diagnostic criteria outlined by the Movement Disorders Society (MDS) [14]. For the PD patients, Hoehn-Yahr staging and their disease duration were recorded. A family history of PD was also recorded. Parkinsonism patients with secondary causes, such as inflammatory, drug-induced, vascular and toxin-induced parkinsonism, were excluded. Patients with parkinsonism with other neurodegenerative diseases, such as Wilson’s disease, progressive supranuclear palsy, cerebral-basal degeneration and multiple system atrophy, were also excluded. This study was approved by the ethics committee of Ren Ji Hospital.

Evaluation

Each PD patient included in this study received an evaluation including the following rating scales: Unified PD Rating Scale provided by the Movement Disorders Society (MDS-UPDRS) was used to assess the status of PD [15]. The Mini-Mental State Examination (MMSE) and Beijing version of the Montreal Cognitive Assessment (MoCA) were adopted to assess cognitive function. The Sniffin’ Sticks 16 (SS-16) was used to assess olfactory function [16]. The Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale were used to assess anxiety and depression, respectively. The non-motor symptoms scale (NMSS) was used to assess non-motor symptoms. The Scales for Outcomes in Parkinson’s disease-Autonomic questionnaire (SCOPA-AUT) was used to assess autonomic symptoms. The 39-item Parkinson’s Disease Questionnaire (PDQ-39) was used to assess the quality of life of the PD patients. The researchers received strict training regarding the use of these scales before assessing the PD patients. We also documented the presence (yes/no) of the following symptoms that were assessed by two individual neurologists: hallucination, apathy, excessive daytime sleepiness, pain, frequent urination, constipation, postural hypotension, sialorrhea, restless legs syndrome (RLS), delusion, double vision, decreased attention, decreased recent memory, nycturia, sexual dysfunction, hypogeusia, change in weight, daytime sweatiness, nocturnal sweatiness, urgent urination or urinary incontinence, sensitivity to light, sensitivity to cold, sensitivity to hot, anxiety, depression, and probable rapid eye movement sleep behaviour disorder (RBD). Probable RBD was diagnosed via the RBD screening questionnaire [17]. We followed the method for detecting NMD3 rs34016896 described by Li and colleagues [18].

Statistics

The R stats (version 3.5.1) and CATT (version 2.0) packages were used to perform the statistical analyses. Student’s t tests were performed to evaluate the differences in numeric variables between NMD3 carriers and wild types. For comparing categorical variables, chi-square tests were performed. The Cochran-Armitage test was used to assess ordinal variables between NMD3 carriers and wild types and an additive model of NMD3. Logistic regression was used to assess the association between the additive model/dominant model/recessive model/overdominant model of NMD3 and clinical phenotypes. The odds ratio (OR) and its 95% confidence intervals (CI) were also used. We also adjusted for age, sex and Hoehn-Yahr staging results.

Results

There were 217 PD patients included in this study. SNPs of two PD patients failed to be detected. In all, there were 39 NMD3 wild types and 178 NMD3 carriers in our study. The minor allele frequency in our group was 0.41, which is similar to a previous genetic association study in southeastern China [11]. There was no difference in age, sex, disease duration, family history, and Hoehn-Yahr staging between the two groups. In the NMD3 wild-type group, the age was 55.69 ± 10.24 years (mean ± SD), and 17 (43.59%) females were included in this group. In the NMD3 carrier group, the average age was 57.03 ± 10.16 years (mean ± SD), and 73 (41.01%) females were included in this group. There were no differences in the total scores on the NMSS, SCOPA-AUT, or PDQ-39 between the two groups. Cognitive function assessed by the MMSE and MoCA of the NMD3 wild types was better than the NMD3 carriers (MMSE: p = 0.042, NMD3 wild type: 27.44 ± 2.89, NMD3 carriers: 26.31 ± 3.79; MoCA: p = 0.005, NMD3 wild type: 23.15 ± 4.20, NMD3 carriers: 20.75 ± 6.68) (Table 1).

Table 1 Demographic data and symptoms in PD patients involved in this study

The presence of hallucination, postural hypotension, and delusion were associated with the additive model (hallucination: p = 0.025; postural hypotension: p = 0.007; and delusion: p = 0.038). In addition, trends in the presence of apathy, decreased recent memory and weight change were found under the additive model (apathy: p = 0.092; decreased recent memory: p = 0.064; and change in weight: p = 0.073) (Table 2).

Table 2 The association between symptoms and genetic models (additive and dominant models) of NMD3 rs34016896

Under the dominant model, the presence of postural hypotension was found (p = 0.052, OR: 2.38, CI: 1.05–6.16, before adjustment; p = 0.050, OR: 2.43, CI: 1.05–6.38, after adjustment) (Table 2).

Under the recessive model, the presence of hallucination, apathy, postural hypotension and delusion were found (hallucination: p = 0.012, OR: 2.96, CI: 1.29–7.10, before adjustment; p = 0.014, OR: 2.95, CI: 1.26–7.21, after adjustment; apathy: p = 0.011, OR: 2.06, CI: 1.18–3.61, before adjustment; p = 0.012, OR: 2.07, CI: 2.28–3.67, after adjustment; postural hypotension: p = 0.017, OR: 2.04, CI: 1.14–3.68, before adjustment; p = 0.016, OR: 2.08, CI: 1.15–3.82, after adjustment; delusion: p = 0.014, OR: 3.94, CI: 1.38–12.92, before adjustment; p = 0.012, OR: 4.41, 1.46–15.47, after adjustment). Trends for decreased attention, decreased recent memory, hypogeusia and change in weight were associated with the recessive model (decreased attention: p = 0.068, OR: 1.76, CI: 0.58–3.02, before adjustment; p = 0.075, OR: 1.78, CI: 0.94–3.38, after adjustment; decreased recent memory: p = 0.075, OR: 1.68, CI: 0.96–3.00, before adjustment; p = 0.069, OR: 1.71, CI: 0.96–3.09, after adjustment; hypogeusia: p = 0.086, OR: 1.63, CI: 0.93–2.85, before adjustment; p = 0.080, OR: 1.65, CI: 0.94–2.89, after adjustment; change in weight: p = 0.097, OR: 0.17, CI: 0.01–0.94, before adjustment; p = 0.089, OR: 0.16, CI: 0.01–0.90, after adjustment) (Table 3).

Table 3 The association between symptoms and genetic models (recessive models) of NMD3 rs34016896

Under the overdominant model, an association with apathy and delusion were found (apathy: p = 0.011, OR: 2.05, CI: 1.19–3.57, before adjustment; p = 0.012, OR: 2.06, CI: 1.18–3.64, after adjustment; delusion: p = 0.048, OR: 3.66, CI: 1.14–16.31, before adjustment; p = 0.035, OR: 4.35, CI: 1.25–20.99, after adjustment.). A trend for an association between hallucination and the overdominant model was found (p = 0.071, OR: 2.32, CI: 0.97–6.17, before adjustment; p = 0.086, OR: 2.26, CI: 0.93–6.13, after adjustment) (Table 4).

Table 4 The association between symptoms and genetic models (overdominant models) of NMD3 rs34016896

We performed the Bonferroni correction following multiple comparisons to adjust p values. After the correction, there were no remaining statistically significant results.

Discussion

Our study found that NMD3 carriers had worse cognitive function. The additive model of NMD3 was associated with hallucination, postural hypotension and delusion. The dominant model of NMD3 was associated with postural hypotension. The recessive model of NMD3 was associated with hallucination, apathy, postural hypotension and delusion. The overdominant model of NMD3 was associated with apathy and delusion. Trends for associations between the additive model of NMD3 and apathy, decreased recent memory and change in weight were found. Trends for associations between the recessive model of NMD3 and decreased attention, decreased recent memory, hypogeusia and change in weight were found. Trends for associations between the overdominant model of NMD3 and hallucination were found. To our knowledge, this is the first study to investigate the association between NMD3 and its clinical symptoms in Chinese PD patients.

NMD3 encodes a cytoplasmic protein for stable 60S ribosomal subunits [19, 20]. The function of ribosomes in the pathogenesis of PD remains unknown. A study revealed that parkin–PARIS (parkin-interacting substrate) played a deleterious role in rRNA transcription in PD patients, which indicated that ribosomes might be involved in the pathogenesis of PD [21]. A possible hypothesis of the function of NMD3 is that the dysfunction or dysregulation of ribosomes produces proteins relevant to PD. More relationships between the eukaryotic ribosome and PD should be discovered.

JM Shulman and colleagues found that NMD3 rs34016896 was associated with nigral neuronal loss and not with Lewy bodies [13]. This research indicated that NMD3 rs34016896 was associated with nigral neurodegeneration rather than the formation of Lewy bodies. Neuronal loss, especially dopaminergic neuronal loss, is associated with the pathogenesis of PD. However, we have little information regarding the details of the type of neurons for neuronal loss. To date, there have been no studies on the clinical phenotype based on the detailed pathological phenotypes. It is difficult to elucidate the impact of neuronal loss on clinical phenotypes. Further research on NMD3-related neuronal loss could uncover the presence of those relevant symptoms.

The strengths of our study are that PD were assessed by a structured scale, which is widely accepted. The diagnosis was based on MDS criteria. We also covered a wide-range assessment examining motor function, non-motor symptoms and quality of life in PD patients.

This study has some weaknesses and limitations. First, we did not perform objective clinical methods, such as electrophysiology, to assess symptoms. Second, we did not perform stratifications due to the small sample size. Third, the sample of our study was small, and our study was a single-centre study. More multicentre and larger studies are warranted.

Conclusions

In conclusion, NMD3 carriers had worse cognitive function. The additive model of NMD3 was associated with hallucination, postural hypotension and delusion. The dominant model of NMD3 was associated with postural hypotension. The recessive model of NMD3 was associated with hallucination, apathy, postural hypotension and delusion. The overdominant model of NMD3 was associated with apathy and delusion. More larger and multicentre studies are warranted. The recessive and overdominant model of NMD3 rs34016896 was associated with cognitive impairment in PD patients.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CI:

confidence interval

MDS:

Movement Disorders Society

MMSE:

Mini-Mental State Examination

MoCA:

Montreal Cognitive Assessment

NMSS:

non-motor symptoms scale

OR:

odds ratio

PARIS:

parkin-interacting substrate

PD:

Parkinson’s disease

PDQ-39:

39-item Parkinson’s Disease Questionnaire

RBD:

rapid eye movement sleep behaviour disorder

RLS:

restless legs syndrome

SCOPA-AUT:

Scales for Outcomes in Parkinson’s disease-Autonomic questionnaire

SS-16:

Sniffin’ Sticks 16

UPDRS:

Unified Parkinson’s Disease Rating Scale

References

  1. Zou YM, Liu J, Tian ZY, Lu D, Zhou YY. Systematic review of the prevalence and incidence of Parkinson’s disease in the People’s Republic of China. Neuropsychiatr Dis Treat. 2015;11:1467–72.

    Article  Google Scholar 

  2. Béné R, Antić S, Budisić M, Lisak M, Trkanjec Z, Demarin V, Podobnik-Sarkanji S. Parkinson’s disease. Acta Clin Croat. 2009;48(3):377–80.

    PubMed  Google Scholar 

  3. Steece-Collier K, Maries E, Kordower JH. Etiology of Parkinson’s disease: genetics and environment revisited. Proc Natl Acad Sci U S A. 2002;99(22):13972–4.

    Article  CAS  Google Scholar 

  4. Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW, Wang L, Züchner S, Konidari I, Wang G, Singer C, Nahab F, Scott B, Stajich JM, Pericak-Vance M, Haines J, Vance JM, Martin ER. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet. 2010;74(2):97–109.

    Article  CAS  Google Scholar 

  5. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H. Common genetic variation in the HLA region is associated with lateonset sporadic Parkinson’s disease. Nat Genet. 2010;42(9):781–5.

    Article  CAS  Google Scholar 

  6. International Parkinson Disease Genomics Consortium, Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón-Sánchez J, Schulte C, Lesage S, Sveinbjörnsdóttir S, Stefánsson K, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW. Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet. 2011;377(9766):641–9.

    Article  Google Scholar 

  7. Blanca Ramírez M, Madero-Perez J, Rivero-Rios P, Martinez-Salvador M, Lara Ordonez AJ, Fernandez B, Fdez E, Hilfiker S. LRRK2 and Parkinson’s disease: from lack of structure to gain of function. Curr Protein Pept Sci. 2017;18(7):677–86.

    Article  Google Scholar 

  8. Siddiqui IJ, Pervaiz N, Abbasi AA. The Parkinson disease gene SNCA: evolutionary and structural insights with pathological implication. Sci Rep. 2016;6:24475.

    Article  CAS  Google Scholar 

  9. Davis MY, Johnson CO, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, Van Deerlin VM, Quinn JF, Chung KA, Peterson-Hiller AL, Rosenthal LS, Dawson TM, Albert MS, Goldman JG, Stebbins GT, Bernard B, Wszolek ZK, Ross OA, Dickson DW, Eidelberg D, Mattis PJ, Niethammer M, Yearout D, Hu SC, Cholerton BA, Smith M, Mata IF, Montine TJ, Edwards KL, Zabetian CP. Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in Parkinson disease. JAMA Neurol. 2016;73(10):1217–24.

    Article  Google Scholar 

  10. Liu ZH, Guo JF, Li K, Wang YQ, Kang JF, Wei Y, Sun QY, Xu Q, Wang DL, Xia K, Yan XX, Xu CS, Tang BS. Analysis of several loci from genome-wide association studies in Parkinson’s disease in mainland China. Neurosci Lett. 2015;587:68–71.

    Article  CAS  Google Scholar 

  11. Chen Y, Cao B, Ou R, Wei Q, Chen X, Zhao B, Wu Y, Song W, Shang HF. Determining the effect of the HNMT, STK39, and NMD3 polymorphisms on the incidence of Parkinson’s disease, amyotrophic lateral sclerosis, and multiple system atrophy in Chinese populations. J Mol Neurosci. 2018;64(4):574–80.

    Article  CAS  Google Scholar 

  12. Malyutin AG, Musalgaonkar S, Patchett S, Frank J, Johnson AW. Nmd3 is a structural mimic of eIF5A, and activates the cpGTPase Lsg1 during 60S ribosome biogenesis. EMBO J. 2017;36(7):854–68.

    Article  CAS  Google Scholar 

  13. Shulman JM, Yu L, Buchman AS, Evans DA, Schneider JA, Bennett DA, De Jager PL. Association of Parkinson disease risk loci with mild parkinsonian signs in older persons. JAMA Neurol. 2014;71(4):429–35.

    Article  Google Scholar 

  14. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591–601.

    Article  Google Scholar 

  15. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N. Movement disorder society UPDRS revision task force. movement disorder society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDSUPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129–70.

    Article  Google Scholar 

  16. Chen W, Chen S, Kang WY, Li B, Xu ZM, Xiao Q, Liu J, Wang Y, Wang G, Chen SD. Application of odor identification test in Parkinson’s disease in China: a matched case-control study. J Neurol Sci. 2012;316(1–2):47–50.

    Article  Google Scholar 

  17. Shen SS, Shen Y, Xiong KP, Chen J, Mao CJ, Huang JY, Li J, Han F, Liu CF. Validation study of REM sleep behavior disorder questionnaire-Hong Kong (RBDQ-HK) in east China. Sleep Med. 2014;15(8):952–8.

    Article  Google Scholar 

  18. Li G, Cui S, Du J, Liu J, Zhang P, Fu Y, He Y, Zhou H, Ma J, Chen S. Association of GALC, ZNF184, IL1R2 and ELOVL7 with Parkinson’s disease in southern Chinese. Front Aging Neurosci. 2018;10:402.

    Article  CAS  Google Scholar 

  19. Ho JH, Johnson AW. NMD3 encodes an essential cytoplasmic protein required for stable 60S ribosomal subunits in Saccharomyces cerevisiae. Mol Cell Biol. 1999;19(3):2389–99.

    Article  CAS  Google Scholar 

  20. Oeffinger M. Joining the interface: a site for Nmd3 association on 60S ribosome subunits. J Cell Biol. 2010;189(7):1071–3.

    Article  CAS  Google Scholar 

  21. Kang H, Shin JH. Repression of rRNA transcription by PARIS contributes to Parkinson’s disease. Neurobiol Dis. 2015;73:220–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the patients who participated in this study.

Funding

This work was supported by grants from the National Natural Science Foundation of China [81801049] and the Minhang District Natural Science Research Project of Shanghai (grant no. 2016MHZ55). The two fundings supported the collection of the PD data.

Author information

Authors and Affiliations

Authors

Contributions

H W and H L collected the PD and control data, performed the statistical analysis and drafted the manuscript. Zq S, Jj T, Sy M and Ty A collected the PD data.

Zz H designed the study, supervised the study, doublechecked the statistical analysis and revised the manuscript. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Zhenzhou He.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Research Ethics Committee, Renji Hospital, Shanghai, China. All participants signed consent forms. It also adhered to international guidelines established for scientific research involving human participants as established by the Declaration of Helsinki and its subsequent amendments.

Consent for publication

Not applicable.

Competing interests

The authors declare that there is no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, H., Li, H., Shi, Z. et al. Association between NMD3 and symptoms of Parkinson’s disease in Chinese patients. BMC Neurol 20, 19 (2020). https://doi.org/10.1186/s12883-019-1574-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12883-019-1574-1

Keywords