Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 Oct 1.
Published in final edited form as: Neurobiol Aging. 2020 Apr 30;94:311.e5–311.e10. doi: 10.1016/j.neurobiolaging.2020.04.016

LRP10 variants in progressive supranuclear palsy

Leonie JM Vergouw a, Shamiram Melhem a, Laura Donker Kaat a,b, Wang Z Chiu a, Demy JS Kuipers b, Guido Breedveld b, Agnita JW Boon c, Li-San Wang d,e,f,g, Adam C Naj d,e,f, Elizabeth Mlynarksi d,e, Laura Cantwell d,e, Marialuisa Quadri b, Owen A Ross h, Dennis W Dickson h, Gerard D Schellenberg d,e,g, John C van Swieten a, Vincenzo Bonifati b, Frank Jan de Jong a,*
PMCID: PMC8281359  NIHMSID: NIHMS1718895  PMID: 32527607

Abstract

The aim of this study was to explore whether variants in LRP10, recently associated with Parkinson's disease and dementia with Lewy bodies, are observed in 2 large cohorts (discovery and validation cohort) of patients with progressive supranuclear palsy (PSP). A total of 950 patients with PSP were enrolled: 246 patients with PSP (n = 85 possible (35%), n = 128 probable (52%), n = 33 definite (13%)) in the discovery cohort and 704 patients with definite PSP in the validation cohort. Sanger sequencing of all LRP10 exons and exon-intron boundaries was performed in the discovery cohort, and whole-exome sequencing was performed in the validation cohort. Two patients from the discovery cohort and 8 patients from the validation cohort carried a rare, heterozygous, and possibly pathogenic LRP10 variant (p.Gly326Asp, p.Asp389Asn, and p.Arg158His, p.Cys220Tyr, p.Thr278Ala, p.Gly306Asp, p.Glu486Asp, p.Arg554*, p.Arg661Cys). In conclusion, possibly pathogenic LRP10 variants occur in a small fraction of patients with PSP and may be overrepresented in these patients compared with controls. This suggests that possibly pathogenic LRP10 variants may play a role in the development of PSP.

Keywords: Genetics, LRP10, Rare variants, Progressive supranuclear palsy

1. Introduction

Progressive supranuclear palsy (PSP) is an adult-onset, progressive neurodegenerative disorder clinically characterized by parkinsonism, vertical supranuclear gaze palsy, and postural instability with falls. Other PSP features include frontal lobe and bulbar dysfunction, and cognitive decline (Litvan et al., 1996b; Respondek et al., 2013). The clinical presentation of PSP is heterogeneous, and 10 different clinical phenotypes have been described in patients with PSP neuropathology (Höglinger et al., 2017). PSP brain pathology includes neurofibrillary tangles, neutrophil threads, tufted astrocytes, neuronal loss, and gliosis in multiple subcortical areas and other regions (Hauw et al., 1994).

PSP is usually considered a sporadic tauopathy of unknown etiology (Im et al., 2015). However, rare familial forms have been reported (Donker Kaat et al., 2009; Fujioka et al., 2014). Mutations in the microtubule-associated protein tau (MAPT) gene have been reported as the likely disease cause in a few pathologically confirmed patients with PSP (Fujioka et al., 2015; Poorkaj et al., 2002). Furthermore, genome-wide association studies have shown associations between PSP and the MAPT, syntaxin-6 (STX6), myelin-associated oligodendrocyte basic protein (MOBP), and eukaryotic translation initiation factor 2-alpha kinase (EIF2AK) genes, modulating the risk of developing PSP (Chen et al., 2018; Sanchez-Contreras et al., 2018). Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have also been implicated in a small number of PSP cases (Ross et al., 2006; Sanchez-Contreras et al., 2017) and are the most common genetic cause of Parkinson's disease (PD) (Healy et al., 2008). Interestingly, pleomorphic neuropathology has been observed in PD patients with LRRK2 mutations, ranging from typical alpha-synuclein–positive pathology (seen in most cases) to PSP-like pathology (Zimprich et al., 2004). Indeed in the original Japanese family, which nominated the linkage region for LRRK2, the affected members presented with tauopathy (Ujiie et al., 2012). Because of these genetic and pathological overlaps between PD and PSP, we hypothesized that variants in the low-density lipoprotein receptor related protein 10 (LRP10) gene, recently associated with PD and dementia with Lewy bodies (Quadri et al., 2018; Vergouw et al., 2019), might also be implicated in PSP. LRP10 is a surface protein, whose function is largely elusive. However, some studies have suggested a role of LRP10 in ligand trafficking between the trans-Golgi network, endosomes, and the plasma membrane. Furthermore, LRP10 has been linked to the metabolism of amyloid-β and α-synuclein (Brodeur et al., 2012; von Einem et al., 2015, 2017).

The aim of this study is to explore whether possibly pathogenic variants in LRP10 are observed in a large Dutch cohort of patients with PSP (discovery cohort) using Sanger sequencing. In addition, we try to validate our findings in a large cohort of patients with PSP (validation cohort) from the United States and Europe using whole-exome sequencing (WES).

2. Methods

2.1. Subjects

Patients with PSP from 2 large cohorts were enrolled in this study. PSP was diagnosed according to the criteria of the National Institute for Neurological Disorders and Stroke/Society for PSP (NINDS-SPSP) (Litvan et al., 1996a). The discovery cohort consisted of 246 patients with PSP enrolled from a large Dutch cohort (Donker Kaat et al., 2007), consecutively collected between 2003 and 2012 (Table 1). Patients were ascertained at the outpatient clinic of the Erasmus Medical Center Rotterdam, at home or at nursing homes. At inclusion, information about patienťs medical and family history and current medical status was collected. Furthermore, neurological examinationwas performed, and a blood sample was collected. The validation cohort consisted of 704 neuropathologically confirmed patients with PSP enrolled form a large cohort of patients from the United States and Europe (Höglinger et al., 2011) (Table 1). These patients were identified from brain banks, research hospitals, and neuropathologists. The study was approved by the relevant Institutional Ethical Authorities, and all participants or legal representatives signed informed consent.

Table 1.

Demographic and clinical characteristics

n = 246 n = 704
Sex, male 127 (52%) 377 (54%)
Diagnosis (NINDS-SPSP)
 Possible PSP 85 (35%) 0 (0%)
 Probable PSP 128 (52%) 0 (0%)
 Definite PSP 33 (13%) 704 (100%)
Age at disease onset, y (n = 246;476) 65.8 (7.5) 68.1 (8.4)
Family history of neurodegenerative diseases (n = 244;0)
 1st degree 71 (29%) NA
 2nd degree 21 (9%) NA
 No 152 (62%) NA
Deceased (n = 244;704) 242 (98%) 704 (100%)
Age at death, y (n = 241;698) 73.7 (7.3) 75.3 (8.2)
Open in a new tab

Values are presented as n (%) or mean (SD).

Key: NINDS-SPSP, National Institute for Neurological Disorders and Stroke/Society for PSP; PSP, progressive supranuclear palsy; NA, not available.

2.2. Genetic analyses

2.2.1. . Genetic analyses in the 2 cohorts

Genomic DNA was isolated from blood in the discovery cohort and from brain tissue in the validation cohort using standard methods. Sanger sequencing was performed for the entire open reading frame and exon-intron boundaries of LRP10 in the discovery cohort (protocol reported by Vergouw et al., 2019). WES was performed in the validation cohort (Supplementary Information). Possibly pathogenic LRP10 variants identified by WES in the validation cohort were validated by Sanger sequencing (Supplementary Information). We considered variants as possibly pathogenic according to the following criteria: (1) heterozygous state; (2) rarity, defined as a frequency <0.1% in the Genome Aggregation Database (GnomAD v2.1); (3) exonic location and non-synonymous, or predicted to affect splicing; and (4) predicted as pathogenic by at least 5 of 11 in silico programs (Supplementary Information).

2.2.2. Additional genetic analyses in possibly pathogenic LRP10 variant carriers in the discovery cohort

WES, multiple ligation-dependent probe amplification (P051-Parkinson mix 1), and C9orf72 repeat expansion analysis were performed in patients who carried possibly pathogenic LRP10 variants to exclude possibly pathogenic variants in other known genes causing parkinsonism or dementia (Supplementary Table 1). The presence of possibly pathogenic variants in known genes causing parkinsonism or dementia in possibly pathogenic LRP10 variant carriers decreases the chance of the LRP10 variant to be truly pathogenic. WES and multiple ligation-dependent probe amplification were performed as reported previously by Vergouw et al. (2019). Details of the methods of the C9orf72 repeat expansion analysis can be found in the Supplementary Information.

3. Results

3.1. Demographic and clinical characteristics of the 2 cohorts

The discovery cohort consisted of 85 (35%) patients with possible PSP, 128 (52%) with probable PSP (52%), and 33 (13%) with definite PSP. The mean disease onset age in this cohort was 65.8 ± 7.5 years and 52% of patients were male; 29% of patients had at least one first-degree relative and 9% had at least one second-degree relative with a neurodegenerative disease. The validation cohort consisted of 704 patients with definite PSP. The mean disease-onset age in this cohort was 68.1 ± 8.4 years (data only available in n = 476), and 54% of patients were male (Table 1).

3.2. Genetic findings

Two possibly pathogenic LRP10 variants were detected in the discovery cohort, each in single patients (p.Gly326Asp and p.Asp389Asn). In the validation cohort, 7 possibly pathogenic LRP10 variants were detected in 8 patients (p.Arg158His, p.Cys220Tyr, p.Thr278Ala, p.Gly306Asp, p.Glu486Asp, p.Arg554*, and p.Arg661Cys; see Table 2 and Supplementary Table S2 for specifications). Supplementary Figure S1A shows the LRP10 gene structure with the location of the identified variants, and Supplementary Figure S1B shows the LRP10 protein structure with the location of the amino acid changes. Other variants in LRP10 which did not fulfill the criteria for possible pathogenicity, as described in Section 2.2.1., are depicted in Supplementary Table S3. Additional WES analysis (average depth of >170× with 99% of the target region covered >20×) in the possibly pathogenic LRP10 variant carriers from the discovery cohort revealed a heterozygous VPS13C variant (p.Gln2546*, absent in GnomAD v2.1) in 1 patient (Supplementary Table S4). No other mutations in genes causing parkinsonism or dementia were found.

Table 2.

Possibly pathogenic LRP10 variants

Genetic information
 Clinical information
Genomic position Nucleotide change Amino acid change Exon Coding effect dbSNP 142 accession number Allele frequency GnomAD (alleles) Functional predictions: Pathogenic (total) Splicing predictions: Deleterious (total) Patient NINDS-SPSP criteria Age at onset (y) Age at death (y)
Discovery cohort
14:23345322 c.1165 G>A p.Asp389Asn 5 Missense rs754181235 0.01% (37) 6/11 n.a. 1 Probable PSP 61 66
14:23345134 c.977 G>A p.Gly326Asp 5 Missense rs547591765 0.006% (14) 6/11 n.a. 2 Possible PSP 55 65
Validation cohort
14:23344630 c.473 G>A p.Arg158His 5 Missense rs764424911 0.005% (13) 6/11 n.a. 1 Definite PSP 68 75
14:23344816 c.659 G>A p.Cys220Tyr 5 Missense rs867533372 . 10/11 n.a. 2 Definite PSP 70 74
14:23344989 c.832 A>G p.Thr278Ala 5 Missense . . 5/11 n.a. 3 Definite PSP 74 87
14:23345074 c.917 G>A p.Gly306Asp 5 Missense rs375748692 0.007% (21) 9/11 n.a. 4 Definite PSP NA 66
5 Definite PSP 74 80
14:23345931a c.1458 G>C p.Glu486Asp 6 Missense rs142130715 0.01% (32) 11/11 0/4 6 Definite PSP 78 83
14:23346254 c.1660 C>T p.Arg554* 7 Stop gain rs201213246 0.01% (28) n.a. n.a. 7 Definite PSP 74 84
14:23346575 c.1981C>T p.Arg661Cys 7 Missense rs771796662 0.004% (10) 8/11 n.a. 8 Definite PSP NA 84
Open in a new tab

The Genome Reference Consortium Human Build 37 (hg19) and NM_014045–4 LRP10 transcript were used.

Splicing prediction programs: SSF, MaxEnt, NNSPLICE, GeneSplicer.

Key: GnomAD, Genome Aggregation Database; NINDS-SPSP, National Institute for Neurological Disorders and Stroke/Society for progressive supranuclear palsy; n.a., not applicable; NA, not available.

a

This variant was not validated by Sanger sequencing because no additional DNA was available.

3.3. Clinical information of possibly pathogenic LRP10 variant carriers

An overview of the clinical information of the possibly pathogenic LRP10 variant carriers is shown in Table 2. Patient 1 from the discovery cohort (LRP10 p.Asp389Asn variant) experienced falls from the age of 61 years, followed by swallowing problems. At the age of 63 years, a mild downward vertical supranuclear gaze palsy, dysarthric speech, reduced arm swing, palatal tremor, and impaired balance, but no clear ataxia, were observed. He had a favorable response to levodopa. At neuropsychological examination, deficits were observed in attention, concentration, and executive functioning. Furthermore, mild memory and naming problems were seen. Brain MRI showed mild parieto-occipital and cerebellar atrophy and hypertrophy of the olivary nuclei. The patient died at the age of 66 years. Family history was negative for parkinsonism, dementia, or motor neuron disease. Brain autopsy was not performed. This patient was diagnosed with probable PSP during life according to the NINDS-SPSP criteria (Litvan et al., 1996a) and can retrospectively be classified as probable PSP with Richardson's syndrome according to the MDS criteria (Höglinger et al., 2017). Patient 2 from the discovery cohort (LRP10 p.Gly326Asp variant) experienced tremor of the right leg from the age of 55 years, followed by falls, rigidity, swallowing, speech, and memory problems from the age of 60 years. At the age of 64 years, vertical supranuclear gaze palsy, bradykinesia, intermittent rest tremor of arms and legs, and balance problems were observed. She had a favorable response to levodopa. Neuropsychological examination showed severe deficits, especially with frontal subcortical and language problems. Brain MRI was unremarkable. The patient died at the age of 65 years. Family history was negative for parkinsonism, dementia, or motor neuron disease. Brain autopsy was not performed. This patient was diagnosed with possible PSP during life according to the NINDS-SPSP criteria (Litvan et al., 1996a) and can retrospectively be classified as probable PSP with predominant parkinsonism according to the MDS criteria (Höglinger et al., 2017).

4. Discussion

In this study, we explored the presence of LRP10 variants in 2 cohorts with a total of 950 PSP patients (discovery cohort n = 246, validation cohort n = 704). The PSP diagnosis was pathologically confirmed in 78% of these patients. Two possibly pathogenic LRP10 variants (p.Gly326Asp and p.Asp389Asn) were identified in 2 patients from the discovery cohort, and 7 possibly pathogenic LRP10 variants (p.Arg158His, p.Cys220Tyr, p.Thr278Ala, p.Gly306Asp, p.Glu486Asp, p.Arg554*, and p.Arg661Cys) were identified in 8 patients from the validation cohort. These variants are very rare, are predicted to be pathogenic by ≥5 in silico programs, and are mostly located in LRP10 exon 5, where other probably pathogenic variants were previously found (Quadri et al., 2018). Interestingly, the frequency of possibly pathogenic LRP10 variants is significantly higher in the validation cohort (8/1408 alleles = 0.6%) compared with a previous published control cohort of patients with abdominal aneurysms (Quadri et al., 2018) (1/1248 alleles = 0.08%; Fisher's exact test p-value 0.04). In addition, the p.Gly306Asp variant has been identified previously in 2 of 2835 patients with PD and 1 of 5343 controls (Kia et al., 2018), the p.Gly326Asp variant in 1 of 264 patients with multiple system atrophy and in no controls (Pihlström et al., 2018), and the p.Glu486Asp variant in 3 of 2835 patients with PD and 1 of 111 patients with dementia with Lewy bodies compared with none in 5343 and 233 controls, respectively (Kia et al., 2018). The p.Arg158His, p.Arg554*, and p.Arg661Cys variants have previously been identified in single controls (Kia et al., 2018; Guerreiro et al., 2018; Pihlström et al., 2018; Supplementary Table S5).

Both patients from the discovery cohort displayed uncommon PSP clinical features. Patient 1 had a palatal tremor, inferior olivary hypertrophy, and cerebellar atrophy. Inferior olivary hypertrophy is observed in 1.5% of pathologically confirmed patients with PSP (Katsuse and Dickson, 2004), but associated palatal tremor is very rare in PSP (Katsuse and Dickson, 2004; Suyama et al., 1997). The syndrome of progressive ataxia and palatal tremor (Mongin et al., 2016) may retrospectively also be considered in patient 1, yet the clinical phenotype is most consistent with PSP. An uncommon feature in patient 2 was the presence of an isolated tremor of the right leg in the first 5 years of the disease. Unfortunately, autopsy studies were not performed in these patients, and therefore, the diagnosis could not be verified at the pathological level. The absence of a family history of PSP or other neurodegenerative disorders in these 2 patients would be compatible with an incomplete penetrance or a de novo occurrence of the LRP10 variants.

Of note, a VPS13C variant (p.Gln2546*) was observed in one LRP10 variant carrier. Mutations in VPS13C are associated with autosomal recessive forms of early-onset parkinsonism (Lesage et al., 2016). In our patient, the variant was found in the heterozygous state and is therefore most likely an incidental finding.

Strengths of this study are the large sample size of the 2 PSP cohorts, the validation of our findings in an independent cohort, and the high percentage of neuropathologically confirmed patients with PSP. Limitations are the lack of screening for LRP10 genomic deletions of multiplications (not detectable by Sanger methods).

In conclusion, this is the first study of LRP10 in 2 large PSP cohorts. We showed that rare, possibly pathogenic LRP10 variants occur in a small but substantial fraction of patients with PSP. Furthermore, possibly pathogenic LRP10 variants may be overrepresented in patients with PSP compared with controls and may therefore play a role in disease pathogenesis. Further studies are warranted to replicate our findings and to study which molecular mechanisms underlie the possible association between LRP10 and PSP.

Supplementary Material

Supp Figure 1
Suppl Info
Suppl Tables

Acknowledgements

The authors gratefully acknowledge support of patients and their families for participating in this study, the CurePSP Society, and the Human Genotyping Facility of the Genetic laboratory of the Department of Internal Medicine at the Erasmus Medical Center for the whole-exome sequencing service in the discovery cohort. This work wassupported bya grantof ZonMw, Netherlands (70-73305-98-102) to FJdJ, and by grants from the Stichting Parkinson Fonds, Netherlands to VB. A subset of validation cohort samples included in this study were brain donors to the brain bank at Mayo Clinic in Jacksonville, which is supported by CurePSP and the Tau Consortium and in part by the Mayo Clinic Florida NINDS Tau Center without Walls Program (U54-NS100693) and the NIH sequencing project (UG3 NS104095). This work was also supported by grants from the NIA/NIH, United States (P01 AG017586) and NINDS/NIH, United States (U54 NS100693)to GDS and agrant from NIA/NIH (R01 AG054060) to ACN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Footnotes

Disclosure statement

The authors declare that there are no conflicts of interest associated with this work.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.neurobiolaging.2020.04.016.

References

  1. Brodeur J, Theriault C, Lessard-Beaudoin M, Marcil A, Dahan S, Lavoie C, 2012. LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer's disease. Mol. Neurodegener. 7, 31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chen JA, Chen Z, Won H, Huang AY, Lowe JK, Wojta K, Yokoyama JS, Bensimon G, Leigh PN, Payan C, Shatunov A, Jones AR, Lewis CM, Deloukas P, Amouyel P, Tzourio C, Dartigues JF, Ludolph A, Boxer AL, Bronstein JM, Al-Chalabi A, Geschwind DH, Coppola G, 2018. Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol. Neurodegener. 13, 41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Donker Kaat L, Boon AJ, Kamphorst W, Ravid R, Duivenvoorden HJ, van Swieten JC, 2007. Frontal presentation in progressive supranuclear palsy. Neurology 69, 723–729. [DOI] [PubMed] [Google Scholar]
  4. Donker Kaat L, Boon AJ, Azmani A, Kamphorst W, Breteler MM, Anar B, Heutink P, van Swieten JC, 2009. Familial aggregation of parkinsonism in progressive supranuclear palsy. Neurology 73, 98–105. [DOI] [PubMed] [Google Scholar]
  5. Fujioka S, Van Gerpen JA, Uitti RJ, Dickson DW, Wszolek ZK, 2014. Familial progressive supranuclear palsy: a literature review. Neurodegener. Dis. 13, 180–182. [DOI] [PubMed] [Google Scholar]
  6. Fujioka S, Sanchez Contreras MY, Strongosky AJ, Ogaki K, Whaley NR, Tacik PM, van Gerpen JA, Uitti RJ, Ross OA, Wszolek ZK, Rademakers R, Dickson DW, 2015. Three sib-pairs of autopsy-confirmed progressive supranuclear palsy. Parkinsonism Relat. Disord. 21, 101–105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Guerreiro R, Orme T, Neto JL, Bras J, International DLBGC, 2018. LRP10 in alpha-synucleinopathies. Lancet Neurol. 17, 1032–1033. [DOI] [PubMed] [Google Scholar]
  8. Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL, McKee A, Tabaton M, Litvan I, 1994. Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44, 2015–2019. [DOI] [PubMed] [Google Scholar]
  9. Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW, International LRRK2 Consortium, 2008. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 7, 583–590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Höglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, Group PSPGS, Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Muller U, Schellenberg GD, 2011. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat. Genet. 43, 699–705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Höglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, Mollenhauer B, Muller U, Nilsson C, Whitwell JL, Arzberger T, Englund E, Gelpi E, Giese A, Irwin DJ, Meissner WG, Pantelyat A, Rajput A, van Swieten JC, Troakes C, Antonini A, Bhatia KP, Bordelon Y, Compta Y, Corvol JC, Colosimo C, Dickson DW, Dodel R, Ferguson L, Grossman M, Kassubek J, Krismer F, Levin J, Lorenzl S, Morris HR, Nestor P, Oertel WH, Poewe W, Rabinovici G, Rowe JB, Schellenberg GD, Seppi K, van Eimeren T, Wenning GK, Boxer AL, Golbe LI, Litvan I, Movement Disorder Society-endorsed PSP Study Group, 2017. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov. Disord. 32, 853–864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Im SY, Kim YE, Kim YJ, 2015. Genetics of progressive supranuclear palsy. J. Mov. Disord. 8, 122–129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Katsuse O, Dickson DW, 2004. Inferior olivary hypertrophy is uncommon in progressive supranuclear palsy. Acta Neuropathol. 108, 143–146. [DOI] [PubMed] [Google Scholar]
  14. Kia DA, Sabir MS, Ahmed S, Trinh J, Bandres-Ciga S, International Parkinson's Disease Genomics, C., 2018. In alpha-synucleinopathies. Lancet Neurol. 17, 1032. [Google Scholar]
  15. Lesage S, Drouet V, Majounie E, Deramecourt V, Jacoupy M, Nicolas A, Cormier-Dequaire F, Hassoun SM, Pujol C, Ciura S, Erpapazoglou Z, Usenko T, Maurage CA, Sahbatou M, Liebau S, Ding J, Bilgic B, Emre M, Erginel-Unaltuna N, Guven G, Tison F, Tranchant C, Vidailhet M, Corvol JC, Krack P, Leutenegger AL, Nalls MA, Hernandez DG, Heutink P, Gibbs JR, Hardy J, Wood NW, Gasser T, Durr A, Deleuze JF, Tazir M, Destee A, Lohmann E, Kabashi E, Singleton A, Corti O, Brice A, French Parkinson's Disease Genetics Study, International Parkinson's Disease Genomics, Consortium, 2016. Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/parkin-dependent mitophagy. Am. J. Hum. Genet. 98, 500–513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, Goetz CG, Golbe LI, Grafman J, Growdon JH, Hallett M, Jankovic J, Quinn NP, Tolosa E, Zee DS, 1996a. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47, 1–9. [DOI] [PubMed] [Google Scholar]
  17. Litvan I, Agid Y, Jankovic J, Goetz C, Brandel JP, Lai EC, Wenning G, D'Olhaberriague L, Verny M, Chaudhuri KR, McKee A, Jellinger K, Bartko JJ, Mangone CA, Pearce RK,1996b. Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology 46, 922–930. [DOI] [PubMed] [Google Scholar]
  18. Mongin M, Delorme C, Lenglet T, Jardel C, Vignal C, Roze E, 2016. Progressive ataxia and palatal tremor: think about POLG mutations. Tremor Other Hyperkinet Mov 6, 1–2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pihlström L, Schottlaender L, Chelban V, Houlden H, Consortium MSAE, 2018. LRP10 in alpha-synucleinopathies. Lancet Neurol. 17, 1033–1034. [DOI] [PubMed] [Google Scholar]
  20. Poorkaj P, Muma NA, Zhukareva V, Cochran EJ, Shannon KM, Hurtig H, Koller WC, Bird TD, Trojanowski JQ, Lee VM, Schellenberg GD, 2002. An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. Ann. Neurol. 52, 511–516. [DOI] [PubMed] [Google Scholar]
  21. Quadri M, Mandemakers W, Grochowska MM, Masius R, Geut H, Fabrizio E, Breedveld GJ, Kuipers D, Minneboo M, Vergouw LJM, Carreras Mascaro A, Yonova-Doing E, Simons E, Zhao T, Di Fonzo AB, Chang HC, Parchi P, Melis M, Correia Guedes L, Criscuolo C, Thomas A, Brouwer RWW, Heijsman D, Ingrassia AMT, Calandra Buonaura G, Rood JP, Capellari S, Rozemuller AJ, Sarchioto M, Fen Chien H, Vanacore N, Olgiati S, Wu-Chou YH, Yeh TH, Boon AJW, Hoogers SE, Ghazvini M, AS IJ, van IWFJ, Onofrj M, Barone P, Nicholl DJ, Puschmann A, De Mari M, Kievit AJ, Barbosa E, De Michele G, Majoor-Krakauer D, van Swieten JC, de Jong FJ, Ferreira JJ, Cossu G, Lu CS, Meco G, Cortelli P, van de Berg WDJ, Bonifati V, International Parkinsonism Genetics Network, 2018. LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study. Lancet Neurol. 17, 597–608. [DOI] [PubMed] [Google Scholar]
  22. Respondek G, Roeber S, Kretzschmar H, Troakes C, Al-Sarraj S, Gelpi E, Gaig C, Chiu WZ, van Swieten JC, Oertel WH, Hoglinger GU, 2013. Accuracy of the National Institute for Neurological Disorders and Stroke/Society for Progressive Supranuclear Palsy and neuroprotection and natural history in Parkinson plus syndromes criteria for the diagnosis of progressive supranuclear palsy. Mov. Disord. 28, 504–509. [DOI] [PubMed] [Google Scholar]
  23. Ross OA, Whittle AJ, Cobb SA, Hulihan MM, Lincoln SJ, Toft M, Farrer MJ, Dickson DW, 2006. Lrrk2 R1441 substitution and progressive supranuclear palsy. Neuropathol. Appl. Neurobiol. 32, 23–25. [DOI] [PubMed] [Google Scholar]
  24. Sanchez-Contreras M, Heckman MG, Tacik P, Diehl N, Brown PH, Soto-Ortolaza AI, Christopher EA, Walton RL, Ross OA, Golbe LI, Graff-Radford N, Wszolek ZK, Dickson DW, Rademakers R, 2017. Study of LRRK2 variation in tauopathy: progressive supranuclear palsy and corticobasal degeneration. Mov. Disord. 32, 115–123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sanchez-Contreras MY, Kouri N, Cook CN, Serie DJ, Heckman MG, Finch NA, Caselli RJ, Uitti RJ, Wszolek ZK, Graff-Radford N, Petrucelli L, Wang LS, Schellenberg GD, Dickson DW, Rademakers R, Ross OA, 2018. Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol. Neurodegener. 13, 37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Suyama N, Kobayashi S, Isino H, Iijima M, Imaoka K, 1997. Progressive supranuclear palsy with palatal myoclonus. Acta Neuropathol. 94, 290–293. [DOI] [PubMed] [Google Scholar]
  27. Ujiie S, Hatano T, Kubo S, Imai S, Sato S, Uchihara T, Yagishita S, Hasegawa K, Kowa H, Sakai F, Hattori N, 2012. LRRK2 I2020T mutation is associated with tau pathology. Parkinsonism Relat. Disord. 18, 819–823. [DOI] [PubMed] [Google Scholar]
  28. Vergouw LJM, Ruitenberg A, Wong TH, Melhem S, Breedveld GJ, Criscuolo C, De Michele G, de Jong FJ, Bonifati V, van Swieten JC, Quadri M, 2019. LRP10 variants in Parkinson's disease and dementia with Lewy bodies in the South-West of The Netherlands. Parkinsonism Relat. Disord. 65, 243–247. [DOI] [PubMed] [Google Scholar]
  29. von Einem B, Wahler A, Schips T, Serrano-Pozo A, Proepper C, Boeckers TM, Rueck A, Wirth T, Hyman BT, Danzer KM, Thal DR, von Arnim CA, 2015. The golgi-localized gamma-ear-containing ARF-binding (GGA) proteins alter amyloid-beta precursor protein (APP) processing through interaction of their GAE domain with the beta-site APP cleaving enzyme 1 (BACE1). PLoS One 10, e0129047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. von Einem B, Eschbach J, Kiechle M, Wahler A, Thal DR, McLean PJ, Weishaupt JH, Ludolph AC, von Arnim CAF, Danzer KM, 2017. The Golgi-localized, gamma ear-containing, ARF-binding (GGA) protein family alters alpha synuclein (alpha-syn) oligomerization and secretion. Aging (Albany NY) 9,1677–1697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T, 2004. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supp Figure 1
NIHMS1718895-supplement-Supp_Figure_1.jpg (195.8KB, jpg)
Suppl Info
NIHMS1718895-supplement-Suppl_Info.docx (48.7KB, docx)
Suppl Tables
NIHMS1718895-supplement-Suppl_Tables.docx (46.5KB, docx)

RESOURCES