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Nerve cells immunoreactive for p62 in select hypothalamic and brainstem nuclei of controls and Parkinson’s disease cases

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Abstract

The protein p62 plays an important role in the proteasomal and/or autophagic clearance of misfolded and aggregation-prone proteins. Immunoreactivity for p62, however, not only characterizes pathological proteinaceous inclusions but also occurs in the form of homogeneous nerve cell labeling in brains of both healthy and diseased individuals, e.g., in the vagal dorsal motor nucleus and other subcortical nuclei. In sporadic Parkinson’s disease (PD), the pathological process initially involves preganglionic neurons of the parasympathetic and sympathetic system and probably advances caudo-rostrally from there along the neuroaxis. Since all subsequently affected nuclei (lower raphe nuclei, magnocellular reticular formation, locus coeruleus, and central subnucleus of the amygdala) generate descending projections that terminate in the vagal dorsal motor nucleus and intermediolateral column, it has been conjectured that retrograde axonal transport and transsynaptic transmission of a pathogen contribute to the pathogenesis of PD. The hypothalamic paraventricular nucleus also sends projections to the preganglionic nuclei under consideration and, thus, should belong to the nuclei endangered by the pathological process. However, it remains uninvolved for the duration of the disorder. For this reason, we performed a retrospective study of the relevant nuclei in a cohort of 36 individuals, including 17 with clinically documented PD, one case with incidental Lewy body disease (ILBD), and 18 controls using p62-immunocytochemistry. Remarkably, the neurosecretory cells of the paraventricular nucleus were among the sites showing homogeneous p62-immunolabeling with the greatest consistency. Its p62-immunoreactive profile may indicate that the hypothalamic paraventricular nucleus is somehow capable of effectively metabolizing misfolded proteins and/or preventing their aggregation.

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References

  • Angot E, Brundin P (2009) Dissecting the potential molecular mechanisms underlying alpha-synuclein cell-to-cell transfer in Parkinson’s disease. Parkinsonism Relat Disord 15(Suppl 3):S143–S147

    Article  PubMed  Google Scholar 

  • Beach TG, Adler CH, Sue LI, Vedders L, Lue LF, White CL III, Akiyama H, Caviness JN, Shill HA, Sabbagh MN, Walker DG, Consortium Arizona Parkinson’s Disease (2010) Multi-organ distribution of phosphorylate α-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119:689–702

    Article  PubMed  CAS  Google Scholar 

  • Bloch A, Probst A, Bissig H, Adams H, Tolnay M (2006) α-Synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol 12:284–295

    Article  Google Scholar 

  • Braak H, Braak E (1991a) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  PubMed  CAS  Google Scholar 

  • Braak H, Braak E (1991b) Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1:213–216

    Article  PubMed  CAS  Google Scholar 

  • Braak H, Braak E (1992) Anatomy of the human hypothalamus (chiasmatic and tuberal region). Progr Brain Res 93:3–16

    Article  CAS  Google Scholar 

  • Braak H, Del Tredici K (2009) Neuroanatomy and pathology of sporadic Parkinson’s disease. Adv Anat Embryol Cell Biol 201:1–119

    PubMed  Google Scholar 

  • Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E (2003a) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–210

    Article  PubMed  Google Scholar 

  • Braak H, Rüb U, Gai WP, Del Tredici K (2003b) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110:517–536

    Article  PubMed  CAS  Google Scholar 

  • Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134

    Article  PubMed  Google Scholar 

  • Braak H, Sastre M, Bohl JRE, de Vos RAI, Del Tredici K (2007) Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 113:421–429

    Article  PubMed  Google Scholar 

  • Casado B, Pannell LK, Iadarola P, Baraniuk JN (2005) Identification of human nasal mucous protein using proteomics. Proteomics 5:2949–2959

    Article  PubMed  CAS  Google Scholar 

  • Cechetto DF, Saper CB (1988) Neurochemical organization of the hypothalamic projection to the spinal cord in the rat. J Comp Neurol 272:579–604

    Article  PubMed  CAS  Google Scholar 

  • Del Tredici K, Rüb U, de Vos RAI, Bohl JRE, Braak H (2002) Where does Parkinson’s disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426

    PubMed  Google Scholar 

  • Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 106:13010–13015

    Article  PubMed  CAS  Google Scholar 

  • Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK, Litvan I (2009) Diagnostic criteria for the neuropathological assessment of Parkinson disease. Lancet Neurol 8:1150–1157

    Article  PubMed  CAS  Google Scholar 

  • Dickson DW, Uchikado H, Fujishiro H, Tsuboi Y (2010) Evidence in favor of Braak staging of Parkinson’s disease. Mov Disord 25(Suppl 1):S78–S82

    Article  PubMed  Google Scholar 

  • Fahn S (2003) Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci 991:1–14

    Article  PubMed  CAS  Google Scholar 

  • Gal J, Strom AL, Kilty R, Zhang F, Zhu H (2007) p62 accumulates and enhances aggregate formation in model systems of familial amyotrophic lateral sclerosis. J Biol Chem 282:11068–11077

    Article  PubMed  CAS  Google Scholar 

  • Gelb DJ, Oliver E, Gilman S (1999) Diagnostic criteria for Parkinson’s disease. Arch Neurol 56:33–39

    Article  PubMed  CAS  Google Scholar 

  • Goedert M (2001) The significance of tau and α-synuclein inclusions in neurodegenerative diseases. Curr Opin Genet Develop 11:343–351

    Article  CAS  Google Scholar 

  • Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599–614

    Article  PubMed  CAS  Google Scholar 

  • Hosoya Y (1980) The distribution of spinal projection neurons in the hypothalamus of the rat, studied with the HRP method. Exp Brain Res 40:79–87

    Article  PubMed  CAS  Google Scholar 

  • Jellinger KA (1991) Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 14:153–197

    Article  PubMed  CAS  Google Scholar 

  • Jellinger KA (1999) Post mortem studies in Parkinson’s disease––is it possible to detect brain areas for specific symptoms? J Neurol Transm Suppl 56:1–29

    CAS  Google Scholar 

  • Jellinger KA (2001) The pathology of Parkinson’s disease. Adv Neurol 86:55–72

    PubMed  CAS  Google Scholar 

  • Jellinger KA, Mizuno Y (2003) Parkinson’s disease. In: Dickson DW (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropathol Press, Basel, pp 159–187

    Google Scholar 

  • Kingsbury A, Bandopadhyay R, Silveira-Moriyama L, Ayling H, Callis C, Poewe W, Lees AJ (2010) Brain stem pathology in Parkinson’s disease: an evaluation of the Braak staging model. Mov Disord. doi:10.1002/mds.23305

  • Klos KJ, Ahlskog JE, Josephs KA, Apaydin H, Parisi JE, Boeve BF, DeLucia MW, Dickson DW (2006) α-Synuclein pathology in the spinal cord of neurologically asymptomatic aged individuals. Neurology 66:1100–1102

    Article  PubMed  CAS  Google Scholar 

  • Klosen P, Maessen X, de Aguilar P (1993) PEG embedding for immunocytochemistry: application to the analysis of immunoreactivity loss during histological processing. J Histochem Cytochem 41:455–463

    Article  PubMed  CAS  Google Scholar 

  • Koutcherov Y, Mai JK, Ashwell KWS, Paxinos G (2000) Organization of the human paraventricular hypothalamic nucleus. J Comp Neurol 423:299–318

    Article  PubMed  CAS  Google Scholar 

  • Kuusisto E, Salminen A, Alafuzoff I (2002) Early accumulation of p62 in neurofibrillary tangles in Alzheimer’s disease: possible role in tangle formation. Neuropathol Appl Neurobiol 28:228–237

    Article  PubMed  CAS  Google Scholar 

  • Kuusisto E, Parkkinen I, Alafuzoff I (2003) Morphogenesis of nigral inclusions: dissimilar incorporation of alpha-synuclein, ubiquitin, and use of p62. J Neuropathol Exp Neurol 62:1241–1253

    PubMed  CAS  Google Scholar 

  • Kuusisto E, Kauppinen T, Alafuzoff I (2008) Use of p62/SQSTM1 antibodies for neuropathological diagnosis. Neuropathol Appl Neurobiol 34:169–180

    Article  PubMed  CAS  Google Scholar 

  • Lee VMY, Giasson BI, Trojanowski JQ (2004) More than just two peas in a pod: common amyloidogenic properties of tau and α-synuclein in neurodegenerative diseases. Trends Neurosci 27:129–134

    Article  PubMed  CAS  Google Scholar 

  • Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Björklund A, Widner H, Revesz T, Lindvall O, Brundin P (2008) Lewy bodies in grafted neurons in people with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503

    Article  PubMed  CAS  Google Scholar 

  • Litvan I, Bhatia KP, Burn DJ et al (2003) Movement Disorders Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 18:476–486

    Google Scholar 

  • Loewy AD (1981) Descending pathways to the sympathetic and parasympathetic preganglionic neurons. J Auton Nerv Syst 3:265–275

    Article  PubMed  CAS  Google Scholar 

  • Loewy AD (1991) Forebrain nuclei involved in autonomic control. Prog Brain Res 87:253–268

    Article  PubMed  CAS  Google Scholar 

  • Luiten PGM, ter Horst GJ, Karst H, Stefens AB (1985) The course of paraventricular hypothalamic efferents to autonomic structures in medulla and spinal cord. Brain Res 329:374–378

    Article  PubMed  CAS  Google Scholar 

  • McBride PA, Schulz-Schaeffer WJ, Donaldson M et al (2001) Early spread of scrapie from the gastrointestinal tract to the central nervous system involves autonomic fibers of the splanchnic and vagus nerves. J Virol 75:9320–9327

    Article  PubMed  CAS  Google Scholar 

  • Moscat J, Diaz-Meco MT, Wooten MW (2007) Signal intensification and diversification through the p62 scaffold protein. Trends Biochem Sci 32:93–100

    Article  Google Scholar 

  • Nilaver G, Zimmerman EA, Wilkins J, Michaelis J, Hoffman D, Silberman AJ (1980) Magnocellular hypothalamic projections to the lower brainstem and spinal cord of the rat. Neuroendocrinol 30:150–158

    Article  CAS  Google Scholar 

  • Olanow CW, McNaught KS (2006) Ubiquitin–proteasome system and Parkinson’s disease. Mov Disord 21:1806–1823

    Article  PubMed  Google Scholar 

  • Olanow CW, Stern MB, Sethi KP (2009) The scientific and clinical basis for the treatment of Parkinson disease. Neurology 72(Suppl 4):S1–S136

    Article  PubMed  Google Scholar 

  • Ono T, Nishino H, Sasaka K, Muramoto K, Yano I, Simpson A (1978) Paraventricular nucleus connections to spinal cord and pituitary. Neurosci Lett 10:141–146

    Article  PubMed  CAS  Google Scholar 

  • Pan T, Kondo S, Le W, Jankovic J (2008) The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain 131:1969–1978

    Article  PubMed  Google Scholar 

  • Phillips RJ, Walter GC, Wilder SL, Baronowsky EA, Powley TL (2008) Alpha-synuclein immunopositive myenteric neurons and vagal preganglionic terminals: autonomic pathway implicated in Parkinson’s disease? Neuroscience 153:733–750

    Article  PubMed  CAS  Google Scholar 

  • Saper C (1990) Hypothalamus. In: Paxinos G (ed) The human nervous system. Academic Press, Sydney, pp 389–413

    Google Scholar 

  • Saper CB, Loewy AD, Swanson LW, Cowan WM (1976) Direct hypothalamo-autonomic connections. Brain Res 117:305–312

    Article  PubMed  CAS  Google Scholar 

  • Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW (2004) Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 24:8055–8068

    Article  PubMed  CAS  Google Scholar 

  • Seibenhener ML, Geetha T, Wooten MW (2007) Sequestosome 1/p62––more than just a scaffold. FEBS Lett 581:175–179

    Article  PubMed  CAS  Google Scholar 

  • Sofroniew MV, Schrell U (1981) Evidence for a direct projection from oxytocin and vasopressin neurons in the hypothalamic paraventricular nucleus to the medulla oblongata: immunohistochemical visualization of both the horseradish peroxidase transported and the peptide produced by the same neurons. Neurosci Lett 22:211–217

    Article  Google Scholar 

  • Swanson LW (1977) Immunohistochemical evidence for a neurophysin-containing autonomic pathway arising in the paraventricular nucleus of the hypothalamus. Brain Res 128:346–353

    Article  PubMed  CAS  Google Scholar 

  • Swanson LW, Kuypers HGJM (1980) The paraventricular nucleus of the hypothalamus: cytoarchitectonic subdivisions and organization of projections to the pituitary, dorsal vagal complex, and spinal cord as demonstrated by retrograde fluorescence double-labeling methods. J Comp Neurol 194:555–570

    Article  PubMed  CAS  Google Scholar 

  • Swanson LW, McKellar S (1979) The distribution of oxytocin- and neurophysin-stained fibers in the spinal cord of the rat and monkey. J Comp Neurol 188:87–106

    Article  PubMed  CAS  Google Scholar 

  • Swanson LW, Sawchenko PE (1983) Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Ann Rev Neurosci 6:269–324

    Article  PubMed  CAS  Google Scholar 

  • Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of Abeta deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800

    PubMed  Google Scholar 

  • Trojanowski JQ, Lee VMY (2000) “Fatal attractions” of proteins. A comprehensive hypothetical mechanism underlying Alzheimer’s disease and other neurodegenerative disorders. Ann NY Acad Sci 924:62–67

    Article  PubMed  CAS  Google Scholar 

  • Wooten MW, Hu X, Babu JR, Seibenhener MI, Geetha T, Paine MG, Wooten MC (2006) Signaling, polyubiquitination, trafficking, and inclusions: sequestosome 1/p62’s role in neurodegenerative disease. J Biomed Biotechnol 2006:1–12

    Article  Google Scholar 

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Acknowledgments

This study was supported by the German Research Council (Deutsche Forschungsgemeinschaft) and the Michael J. Fox Foundation for Parkinson’s Research (New York City, USA). The Braak Collection (Goethe University, Frankfurt am Main) supplied autopsy material. The skillful technical assistance of Ms. Siegrid Baumann, Ms. Gabriele Ehmke, Ms. Verena Hofmann (immunohistochemistry) and Mr. Stephan Mayer (graphics) is gratefully acknowledged. For Prof. Kurt Jellinger, in honor of his 80th birthday and in recognition of his achievements.

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  1. Clinical Neuroanatomy, Department of Neurology, Center for Clinical Research, University of Ulm, Helmholtzstrasse 8/1, 89081, Ulm, Germany

    Heiko Braak & Kelly Del Tredici

  2. Laboratory for Neuropathology, Institute of Pathology, University of Ulm, Ulm, Germany

    Dietmar R. Thal

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  1. Heiko Braak
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Correspondence to Heiko Braak.

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Braak, H., Thal, D.R. & Del Tredici, K. Nerve cells immunoreactive for p62 in select hypothalamic and brainstem nuclei of controls and Parkinson’s disease cases. J Neural Transm 118, 809–819 (2011). https://doi.org/10.1007/s00702-010-0508-2

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