Here we prioritize as multisystem Lewy body disease (MLBD) those genetic forms of Parkinson's disease that point the way toward a mechanistic understanding of the majority of sporadic disease. Pathological diagnosis of genetic subtypes offers the prospect of distinguishing different mechanistic trajectories with a common mutational etiology, differing outcomes from varying allelic bases, and those disease-associated variants that can be used in gene-environment analysis. Clearly delineating parkinsonian disorders into subclasses on the basis of molecular mechanisms with well-characterized outcome expectations is the basis for refining these forms of neurodegeneration as research substrate through the use of cell models derived from affected individuals while ensuring that clinically collected data can be used for therapeutic decisions and research without increasing the noise and confusion engendered by the collection of data against a range of historically defined criteria.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Molecular Neurodegeneration Open Access 21 June 2021
npj Parkinson's Disease Open Access 23 February 2018
npj Parkinson's Disease Open Access 05 September 2017
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Greenfield, J.G. & Bosanquet, F.D. The brain-stem lesions in Parkinsonism. J. Neurol. Neurosurg. Psychiatry 16, 213–226 (1953).
Cotzias, G.C. L-dopa for Parkinsonism. N. Engl. J. Med. 278, 630 (1968).
Langston, J.W., Ballard, P., Tetrud, J.W. & Irwin, I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979–980 (1983).
Polymeropoulos, M.H. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).
Singleton, A.B., Farrer, M.J. & Bonifati, V. The genetics of Parkinson's disease: progress and therapeutic implications. Mov. Disord. 28, 14–23 (2013).
Langston, J.W. The Parkinson's complex: parkinsonism is just the tip of the iceberg. Ann. Neurol. 59, 591–596 (2006).
Meissner, W.G. When does Parkinson's disease begin? From prodromal disease to motor signs. Rev. Neurol. (Paris) 168, 809–814 (2012).
Lewy, F.H. Paralysis Agitans. I. Pathologische Anatomie (Springer, Berlin, 1912).
Herzog, E. Histopathologische Veränderungen im Sympathicus und ihre Bedeutung. Dtsch. Z. Nervenheilkd. 107, 75–80 (1928).
Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H. & Del Tredici, K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 318, 121–134 (2004).
Braak, H. et al. Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages). J. Neurol. 249 (Suppl. 3), III1–III5 (2002).
Savica, R., Rocca, W.A. & Ahlskog, J.E. When does Parkinson disease start? Arch. Neurol. 67, 798–801 (2010).
Del Tredici, K., Rub, U., De Vos, R.A., Bohl, J.R. & Braak, H. Where does parkinson disease pathology begin in the brain? J. Neuropathol. Exp. Neurol. 61, 413–426 (2002).
Kosaka, K., Yoshimura, M., Ikeda, K. & Budka, H. Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree—a new disease? Clin. Neuropathol. 3, 185–192 (1984).
Hishikawa, N., Hashizume, Y., Yoshida, M. & Sobue, G. Clinical and neuropathological correlates of Lewy body disease. Acta Neuropathol. 105, 341–350 (2003).
Goldstein, D.S. Cardiac denervation in patients with Parkinson disease. Cleve. Clin. J. Med. 74 (Suppl. 1), S91–S94 (2007).
Gelpi, E. et al. Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov. Disord. 29, 1010–1018 (2014).
Klein, C. & Westenberger, A. Genetics of Parkinson's disease. Cold Spring Harb. Perspect. Med. 2, a008888 (2012).
Nalls, M.A. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat. Genet. 46, 989–993 (2014).
Richards, C.S. et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet. Med. 10, 294–300 (2008).
Iritani, S., Tsuchiya, K., Arai, T., Akiyama, H. & Ikeda, K. An atypical autopsy case of Lewy body disease with clinically diagnosed major depression: a clinical, radiological and pathological study. Neuropathology 28, 652–659 (2008).
Kalia, L.V. et al. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 72, 100–105 (2015).
Quattrone, A. et al. Myocardial 123metaiodobenzylguanidine uptake in genetic Parkinson's disease. Mov. Disord. 23, 21–27 (2008).
Chen, Y. et al. Quantitative and fiber-selective evaluation of pain and sensory dysfunction in patients with Parkinson's disease. Parkinsonism Relat. Disord. 21, 361–365 (2015).
Hamza, T.H. et al. Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. PLoS Genet. 7, e1002237 (2011).
Goldman, S.M. et al. Genetic modification of the association of paraquat and Parkinson's disease. Mov. Disord. 27, 1652–1658 (2012).
Langston, J.W., Langston, E.B. & Irwin, I. MPTP-induced parkinsonism in human and non-human primates–clinical and experimental aspects. Acta Neurol. Scand. Suppl. 100, 49–54 (1984).
Langston, J.W., Quik, M., Petzinger, G., Jakowec, M. & Di Monte, D.A. Investigating levodopa-induced dyskinesias in the parkinsonian primate. Ann. Neurol. 47, S79–S89 (2000).
Schüle, B., Pera, R.A. & Langston, J.W. Can cellular models revolutionize drug discovery in Parkinson's disease? Biochim. Biophys. Acta 1792, 1043–1051 (2009).
Byers, B. et al. SNCA triplication Parkinson's patient's iPSC-derived DA neurons accumulate α-synuclein and are susceptible to oxidative stress. PLoS ONE 6, e26159 (2011).
Nguyen, H.N. et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267–280 (2011).
Flierl, A. et al. Higher vulnerability and stress sensitivity of neuronal precursor cells carrying an alpha-synuclein gene triplication. PLoS ONE 9, e112413 (2014).
Reinhardt, P. et al. Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12, 354–367 (2013).
Chung, C.Y. et al. Identification and rescue of alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342, 983–987 (2013).
Soldner, F. et al. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964–977 (2009).
Seibler, P. et al. Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J. Neurosci. 31, 5970–5976 (2011).
Sánchez-Danés, A. et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol. Med. 4, 380–395 (2012).
Liu, G.H. et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491, 603–607 (2012).
Reyes, J.F. et al. A cell culture model for monitoring alpha-synuclein cell-to-cell transfer. Neurobiol. Dis. 77, 266–275 (2015).
Aboud, A.A. et al. Genetic risk for Parkinson's disease correlates with alterations in neuronal manganese sensitivity between two human subjects. Neurotoxicology 33, 1443–1449 (2012).
Chan, P. et al. Absence of mutations in the coding region of the alpha-synuclein gene in pathologically proven Parkinson's disease. Neurology 50, 1136–1137 (1998).
Chan, P., Tanner, C.M., Jiang, X. & Langston, J.W. Failure to find the alpha-synuclein gene missense mutation (G209A) in 100 patients with younger onset Parkinson's disease. Neurology 50, 513–514 (1998).
Farrer, M. et al. Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann. Neurol. 55, 174–179 (2004).
Tetrud, J.W. & Langston, J.W. The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science 245, 519–522 (1989).
Plasterer, T.N., Stanley, R. & Gombocz, E. Correlation Network Analysis and Knowledge Integration (Wiley-VCH, Weinheim, 2011).
Lynge, E., Sandegaard, J.L. & Rebolj, M. The Danish National Patient Register. Scand. J. Public Health 39, 30–33 (2011).
Nilsson, E., Orwelius, L. & Kristenson, M. Patient-reported outcomes in the Swedish National Quality Registers. J. Intern. Med. doi:10.1111/joim.12409 (26 August 2015).
Jensen, L.J. et al. STRING 8—a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res. 37, D412–D416 (2009).
Mrowka, R., Patzak, A. & Herzel, H. Is there a bias in proteome research? Genome Res. 11, 1971–1973 (2001).
Chouraki, V. & Seshadri, S. Genetics of Alzheimer's disease. Adv. Genet. 87, 245–294 (2014).
Seidel, K. et al. First appraisal of brain pathology owing to A30P mutant alpha-synuclein. Ann. Neurol. 67, 684–689 (2010).
Zarranz, J.J. et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55, 164–173 (2004).
Proukakis, C. et al. A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 80, 1062–1064 (2013).
Kiely, A.P. et al. α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson's disease and multiple system atrophy? Acta Neuropathol. 125, 753–769 (2013).
Kiely, A.P. et al. Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation. Mol. Neurodegener. 10, 41 (2015).
Lesage, S. et al. G51D alpha-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann. Neurol. 73, 459–471 (2013).
Golbe, L.I., Di Iorio, G., Bonavita, V., Miller, D.C. & Duvoisin, R.C. A large kindred with autosomal dominant Parkinson's disease. Ann. Neurol. 27, 276–282 (1990).
Duda, J.E. et al. Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol. 104, 7–11 (2002).
Spira, P.J., Sharpe, D.M., Halliday, G., Cavanagh, J. & Nicholson, G.A. Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann. Neurol. 49, 313–319 (2001).
Markopoulou, K. et al. Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson's disease. Variability in familial Parkinson's disease. Acta Neuropathol. 116, 25–35 (2008).
Yamaguchi, K. et al. Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the alpha-synuclein gene. Acta Neuropathol. 110, 298–305 (2005).
Kasten, M. & Klein, C. The many faces of alpha-synuclein mutations. Mov. Disord. 28, 697–701 (2013).
Garraux, G. et al. Partial trisomy 4q associated with young-onset dopa-responsive parkinsonism. Arch. Neurol. 69, 398–400 (2012).
Nishioka, K. et al. Expanding the clinical phenotype of SNCA duplication carriers. Mov. Disord. 24, 1811–1819 (2009).
Kara, E. et al. A 6.4 Mb duplication of the alpha-synuclein locus causing frontotemporal dementia and Parkinsonism: phenotype-genotype correlations. JAMA Neurol. 71, 1162–1171 (2014).
Konno, T., Ross, O.A., Puschmann, A., Dickson, D.W. & Wszolek, Z.K. Autosomal dominant Parkinson's disease caused by SNCA duplications. Parkinsonism Relat. Disord. doi:10.1016/j.parkreldis.2015.09.007 (3 September 2015).
Obi, T. et al. Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology 70, 238–241 (2008).
Ikeuchi, T. et al. Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia. Arch. Neurol. 65, 514–519 (2008).
Waters, C.H. & Miller, C.A. Autosomal dominant Lewy body parkinsonism in a four-generation family. Ann. Neurol. 35, 59–64 (1994).
Muenter, M.D. et al. Hereditary form of parkinsonism—dementia. Ann. Neurol. 43, 768–781 (1998).
Gwinn-Hardy, K. et al. Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol. 99, 663–672 (2000).
Giordana, M.T. et al. Neuropathology of Parkinson's disease associated with the LRRK2 Ile1371Val mutation. Mov. Disord. 22, 275–278 (2007).
Puschmann, A. et al. First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation. Parkinsonism Relat. Disord. 18, 332–338 (2012).
Martí-Massó, J.F. et al. Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2. Mov. Disord. 24, 1998–2001 (2009).
Wszolek, Z.K. et al. Western Nebraska family (family D) with autosomal dominant parkinsonism. Neurology 45, 502–505 (1995).
Wszolek, Z.K. et al. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 62, 1619–1622 (2004).
Khan, N.L. et al. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 128, 2786–2796 (2005).
Ross, O.A. et al. Lrrk2 and Lewy body disease. Ann. Neurol. 59, 388–393 (2006).
Gomez, A. & Ferrer, I. Involvement of the cerebral cortex in Parkinson disease linked with G2019S LRRK2 mutation without cognitive impairment. Acta Neuropathol. 120, 155–167 (2010).
Silveira-Moriyama, L. et al. Hyposmia in G2019S LRRK2-related parkinsonism: clinical and pathologic data. Neurology 71, 1021–1026 (2008).
Gilks, W.P. et al. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365, 415–416 (2005).
Hasegawa, K. et al. Familial parkinsonism: study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes. Parkinsonism Relat. Disord. 15, 300–306 (2009).
Hasegawa, K. & Kowa, H. Autosomal dominant familial Parkinson disease: older onset of age, and good response to levodopa therapy. Eur. Neurol. 38 Suppl 1, 39–43 (1997).
Chahine, L.M. et al. Clinical and biochemical differences in patients having Parkinson disease with vs without GBA mutations. JAMA Neurol. 70, 852–858 (2013).
Sidransky, E. & Lopez, G. The link between the GBA gene and parkinsonism. Lancet Neurol. 11, 986–998 (2012).
Neumann, J. et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain 132, 1783–1794 (2009).
Poulopoulos, M., Levy, O.A. & Alcalay, R.N. The neuropathology of genetic Parkinson's disease. Mov. Disord. 27, 831–842 (2012).
Langston, J.W. et al. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann. Neurol. 46, 598–605 (1999).
Ahn, T.B., Langston, J.W., Aachi, V.R. & Dickson, D.W. Relationship of neighboring tissue and gliosis to alpha-synuclein pathology in a fetal transplant for Parkinson's disease. Am. J. Neurodegener. Dis. 1, 49–59 (2012).
Koga, S. et al. When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients. Neurology 85, 404–412 (2015).
Fuchs, J. et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 68, 916–922 (2007).
Langston, J.W. et al. Novel alpha-synuclein-immunoreactive proteins in brain samples from the Contursi kindred, Parkinson's, and Alzheimer's disease. Exp. Neurol. 154, 684–690 (1998).
Mak, S.K., Tewari, D., Tetrud, J.W., Langston, J.W. & Schüle, B. Mitochondrial dysfunction in skin fibroblasts from a Parkinson's disease patient with an alpha-synuclein triplication. J. Parkinsons Dis. 1, 175–183 (2011).
Marras, C. et al. Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers. Neurology 77, 325–333 (2011).
Sanders, L.H. et al. LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: reversal by gene correction. Neurobiol. Dis. 62, 381–386 (2014).
Lwin, A., Orvisky, E., Goker-Alpan, O., LaMarca, M.E. & Sidransky, E. Glucocerebrosidase mutations in subjects with parkinsonism. Mol. Genet. Metab. 81, 70–73 (2004).
Farrer, M. et al. Lewy bodies and parkinsonism in families with parkin mutations. Ann. Neurol. 50, 293–300 (2001).
Schüle, B., Byrne, C., Rees, L. & Langston, J.W. Is PARKIN parkinsonism a cancer predisposition syndrome? Neurol. Genet. 1, e31 (15 October 2015).
Doostzadeh, J., Tetrud, J.W., Allen-Auerbach, M., Langston, J.W. & Schüle, B. Novel features in a patient homozygous for the L347P mutation in the PINK1 gene. Parkinsonism Relat. Disord. 13, 359–361 (2007).
Hardy, J. & Lees, A.J. Parkinson's disease: a broken nosology. Mov. Disord. 20 (Suppl. 12), S2–S4 (2005).
Jenner, P. et al. Parkinson's disease—the debate on the clinical phenomenology, aetiology, pathology and pathogenesis. J. Parkinsons Dis. 3, 1–11 (2013).
Berg, D. et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease. Mov. Disord. 29, 454–462 (2014).
Forman, M.S., Lee, V.M. & Trojanowski, J.Q. Nosology of Parkinson's disease: looking for the way out of a quagmire. Neuron 47, 479–482 (2005).
We thank J.M. Cruz-Toledo and R. Stanley for their work on the data integration project and network-based searching, IO Informatics and The Parkinson Alliance/Parkinson's Unity Walk for generous support, and our donors and patients whose support makes this work possible.
The authors declare no competing financial interests.
About this article
Cite this article
Langston, J., Schüle, B., Rees, L. et al. Multisystem Lewy body disease and the other parkinsonian disorders. Nat Genet 47, 1378–1384 (2015). https://doi.org/10.1038/ng.3454
This article is cited by
Molecular Neurodegeneration (2021)
npj Parkinson's Disease (2018)
Impact of Neurodegenerative Diseases on Drug Binding to Brain Tissues: From Animal Models to Human Samples
npj Parkinson's Disease (2017)
Nature Genetics (2016)