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Lewy body

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Photomicrographs of regions of the substantia nigra in this Parkinson's patient show Lewy bodies and Lewy neurites stained immunohistochemically for the protein alpha-synuclein. The two top panels are high-magnification images of abnormal cellular inclusions containing aggregated alpha-synuclein. The two bottom panels are lower magnification images showing the strand-like Lewy neurites along with rounded Lewy bodies of various sizes. Some neuromelanin-laden cells of the substantia nigra also are visible, particularly in the two righthand panels. Stains used: mouse monoclonal alpha-synuclein antibody; counterstained with Mayer's haematoxylin. Scale bar for the top two images is in the upper left panel and for the bottom two images in the lower left panel.

Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside neurons affected by Parkinson's disease, the Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), and also in several other disorders such as multiple system atrophy.[1] The defining proteinaceous component of Lewy bodies is alpha-synuclein (α-synuclein), which aggregates to form Lewy bodies within neuronal cell bodies, and Lewy neurites in neuronal processes (axons or dendrites). In some disorders, alpha-synuclein also forms aggregates in glial cells that are referred to as 'glial cytoplasmic inclusions'; together, diseases involving Lewy bodies, Lewy neurites and glial cytoplasmic inclusions are called 'synucleinopathies'.[2]

Photomicrograph of a Lewy body (indicated by the arrowhead) in a neuron of the substantia nigra from a person with Parkinson's disease (hematoxylin and eosin stain; scale bar=20 microns [0.02mm]).

Lewy bodies appear as spherical masses in the neuronal cytoplasm that can displace other cellular components such as the nucleus and neuromelanin.[3] There are two main kinds of Lewy bodies – brainstem-type (classical) and cortical-type.[4] Classical Lewy bodies occur most commonly in pigmented neurons of the brainstem such as the substantia nigra and locus coeruleus; they are strongly eosinophilic structures ranging from 8-30 microns in diameter, and when viewed with a light microscope they are seen to consist of a dense core that is often surrounded by a pale shell.[4] Electron microscopic analyses found that the core consists of a compact mass of filaments and various particles surrounded by a diffuse corona of radiating filaments.[5] In contrast, cortical-type Lewy bodies are smaller, only faintly eosinophilic, and devoid of a surrounding halo with radial filaments.[4][6] Cortical-type Lewy bodies occur in multiple regions of the cortex and in the amygdala.[4]

History

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The structures that later became known as Lewy bodies were first described in neurons of the substantia nigra by G. Marinesco in 1902.[4] In 1910, Fritz Heinrich Lewy was studying in Berlin for his doctorate.[7] He noticed abnormalities in neurons similar to those described by Marinesco and compared them to earlier findings by Gonzalo Rodríguez Lafora.[8] In 1913, Lafora described another case, and credited Lewy with their discovery, naming them cuerpos intracelulares de Lewy (intracellular Lewy bodies).[8] Konstantin Nikolaevich Trétiakoff characterized the inclusions in 1919, calling them corps de Lewy, and he is credited with coining the eponym.[8] In 1923, Lewy published his findings in a book, The Study on Muscle Tone and Movement. Including Systematic Investigations on the Clinic, Physiology, Pathology, and Pathogenesis of Paralysis agitans.[9] Eliasz Engelhardt has argued that Lafora should be credited with the eponym because he named the inclusions six years before Trétiakoff.[8] Nonetheless, Trétiakoff is the primary figure acknowledged for coining the term "Lewy bodies".[8]

According to the Journal of the History of the Neurosciences, Dr. Lewy became interested in the study of neurology because of the discovery by Alois Alzheimer in 1906 that dementia is linked to specific changes in the brain. The article mentions that the third reported case of Alzheimer's disease had histological changes consistent with Lewy body disease.[10]

Cell biology

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Photomicrograph of the dorsal motor nucleus of the vagus nerve (DmX) in a transverse section through the upper medulla that is affected by the abnormal deposition of alpha synuclein in intraneuronal Lewy bodies (righthand panel)[11]

Lewy bodies are composed of the defining protein α-synuclein along with other proteins, such as ubiquitin,[12] neurofilament protein, and alpha B crystallin. Tau proteins may also be present, and Lewy bodies may occasionally be surrounded by neurofibrillary tangles.[13][14] Lewy bodies and neurofibrillary tangles can occasionally co-exist in the same neuron, particularly in the amygdala.[15]

Alpha-synuclein modulates DNA repair processes, including repair of DNA double-strand breaks (DSBs) by the process of non-homologous end joining[16] The repair function of alpha-synuclein appears to be greatly reduced in Lewy body-bearing neurons, and this reduction may trigger cell death. Mutations are the reason behind their damaged repair function.[17] One mutation in particular, in the gene encoding alpha-synuclein, was found to have been passed down from family members with Parkinson's disease.[17] Furthermore, Lewy bodies retrieved from the brains of patients with Lewy body dementia were found to contain alpha-synuclein proteins that were shortened by mutations.[17]

Lewy bodies are believed to represent an aggresome response in the cell.[18] Many diseases result from the aggregation of misfolded proteins, including disorders that are associated with Lewy-type pathology.[19] Aggregation is believed to occur when there is a high amount of misfolded proteins in the ubiquitin-proteasome pathway, which are then brought to a resulting aggresome.[19] Since Lewy bodies are made of ubiquitinated proteins that would be handled in the ubiquitin-proteasome pathway, they may be formed when the degradation pathway is overwhelmed by misfolded proteins.[19] The aggresome thus may be an early stage in the formation of Lewy bodies. The aggregation of alpha-synuclein, like that of many other disease-related proteins[20], is thought to be driven by a prion-like seeding mechanism[21]. According to this hypothesis, normally produced alpha-synuclein is induced to misfold by contact with misfolded alpha-synuclein, resulting in the proliferation and spread of Lewy bodies and Lewy neurites among cells of the nervous system.

There is evidence that a particular protein family, called 14-3-3, plays a role in the formation of both cortical and classical Lewy bodies.[22] 14-3-3 thus is an important protein family with regard to Lewy body-associated diseases.[22]

Cortical Lewy bodies are a distinguishing feature for dementia with Lewy bodies, but they may occasionally be seen in ballooned neurons characteristic of behavioural variant frontotemporal dementia and corticobasal degeneration,[23] as well as in patients with other tauopathies.[24]

Lewy neurites

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Lewy neurites (thread-like structures) and Lewy bodies in a case of Lewy body dementia. Stain: immunohistochemical stain (brown) for alpha-synuclein.

Lewy neurites are abnormal neuronal processes in diseased neurons; they contain granular material and abnormal α-synuclein filaments similar to those found in Lewy bodies.[25] Like Lewy bodies, Lewy neurites are a feature of α-synucleinopathies such as dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy.[26] They occur in many brain regions; in the hippocampal formation they are strongly associated with selective damage to the CA2-CA3 sectors, a characteristic that distinguishes Lewy body diseases from Alzheimer's disease.[4]

See also

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References

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  1. ^ Jellinger KA (September 2007). "More frequent Lewy bodies but less frequent Alzheimer-type lesions in multiple system atrophy as compared to age-matched control brains". Acta Neuropathologica. 114 (3): 299–303. doi:10.1007/s00401-007-0227-4. PMID 17476513. S2CID 32406286.
  2. ^ Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW (2021). "Neuropathology and molecular diagnosis of synucleinopathies". Molecular Neurodegeneration. 16 (1): 83. doi:10.1186/s13024-021-00501-z. PMC 8684287. PMID 34922583.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ Revesz, Tamas; Gray, Francoise; Scaravilli, Francesco (2001). "Chapter 9: Parkinson's Disease". In Duckett, Serge; De La Torre, JC (eds.). Pathology of the Aging Human Nervous System. Oxford University Press. pp. 264–308. ISBN 0-19-513069-3.
  4. ^ a b c d e f Vonsattel, Jean Paul G; Hedley-White, E Tessa (2001). "Chapter 7: Dementia". In Duckett, Serge; De La Torre, JC (eds.). Pathology of the Aging Human Nervous System. Oxford University Press. pp. 156–206. ISBN 0-19-513069-3.
  5. ^ Duchen, LW (1984). "Chapter 1: General Pathology of Neurons and Neuroglia". In Adams, J Hume; Corsellis, JAN; Duchen, LW (eds.). Greenfield's Pathology (Fourth Edition). John Wiley and Sons. pp. 1–52. ISBN 0-471-82307-4.
  6. ^ Mrak, Robert E.; Griffin, W Sue T (October 2007). "Dementia with Lewy bodies: Definition, diagnosis, and pathogenic relationship to Alzheimer's disease". Neuropsychiatric Disease and Treatment. 3 (5): 619–625. PMC 2656298. PMID 19300591.
  7. ^ "Friedrich H. Lewy". Whonamedit?.
  8. ^ a b c d e Engelhardt E (October 2017). "Lafora and Trétiakoff: the naming of the inclusion bodies discovered by Lewy". Arquivos de Neuro-Psiquiatria (Historical article). 75 (10): 751–753. doi:10.1590/0004-282X20170116. PMID 29166468.
  9. ^ Engelhardt E, Gomes MD (2017). "Lewy and his inclusion bodies: Discovery and rejection". Dementia & Neuropsychologia. 11 (2): 198–201. doi:10.1590/1980-57642016dn11-020012. PMC 5710688. PMID 29213511.
  10. ^ García-Albea E, Pérez Trullen JM (December 2003). "The Spanish school of neurology and the first American cases of Alzheimer's disease". Journal of the History of the Neurosciences. 12 (4): 437–445. doi:10.1076/jhin.12.4.437.27919. PMID 15069873. S2CID 40698888.
  11. ^ Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E (March–April 2003). "Staging of brain pathology related to sporadic Parkinson's disease". Neurobiology of Aging. 24 (2): 197–211. doi:10.1016/S0197-4580(02)00065-9. PMID 12498954. S2CID 22798538.
  12. ^ Engelender S (April 2008). "Ubiquitination of alpha-synuclein and autophagy in Parkinson's disease". Autophagy. 4 (3): 372–374. doi:10.4161/auto.5604. PMID 18216494.
  13. ^ Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW (April 2003). "Colocalization of tau and alpha-synuclein epitopes in Lewy bodies". Journal of Neuropathology and Experimental Neurology. 62 (4): 389–397. doi:10.1093/jnen/62.4.389. PMID 12722831.
  14. ^ Arima K, Hirai S, Sunohara N, Aoto K, Izumiyama Y, Uéda K, Ikeda K, Kawai M (October 1999). "Cellular co-localization of phosphorylated tau- and NACP/alpha-synuclein-epitopes in lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies". Brain Research. 843 (1–2): 53–61. doi:10.1016/S0006-8993(99)01848-X. PMID 10528110. S2CID 11144367.
  15. ^ Schmidt ML, Martin JA, Lee VM, Trojanowski JQ (1996). "Convergence of Lewy bodies and neurofibrillary tangles in amygdala neurons of Alzheimer's disease and Lewy body disorders". Acta Neuropathologica. 91 (5): 475–481. doi:10.1007/s004010050454. PMID 8740227. S2CID 19770377.
  16. ^ Schaser AJ, Osterberg VR, Dent SE, Stackhouse TL, Wakeham CM, Boutros SW, et al. (July 2019). "Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders". Scientific Reports. 9 (1): 10919. Bibcode:2019NatSR...910919S. doi:10.1038/s41598-019-47227-z. PMC 6662836. PMID 31358782.
  17. ^ a b c Baba M, Nakajo S, Tu PH, et al. (April 1998). "Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies". The American Journal of Pathology. 152 (4): 879–884. PMC 1858234. PMID 9546347.
  18. ^ Tanaka M, Kim YM, Lee G, Junn E, Iwatsubo T, Mouradian MM (February 2004). "Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective". The Journal of Biological Chemistry. 279 (6): 4625–4631. doi:10.1074/jbc.M310994200. PMID 14627698.
  19. ^ a b c Johnston JA, Ward CL, Kopito RR (December 1998). "Aggresomes: a cellular response to misfolded proteins". The Journal of Cell Biology. 143 (7): 1883–1898. doi:10.1083/jcb.143.7.1883. PMC 2175217. PMID 9864362.
  20. ^ Jucker M, Walker LC (September 2013). "Self-propagation of pathogenic protein aggregates in neurodegenerative diseases". Nature. 501 (7465): 45–51. Bibcode:2013Natur.501...45J. doi:10.1038/nature12481. PMC 3963807. PMID 24005412.
  21. ^ Volpicelli-Daley L, Brundin P (2018). "Prion-like propagation of pathology in Parkinson disease". Handbook of Clinical Neurology. 153: 321–335. doi:10.1186/s13024-021-00501-z. PMC 6625652. PMID 29887143.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ a b Kawamoto Y, Akiguchi I, Nakamura S, Honjyo Y, Shibasaki H, Budka H (March 2002). "14-3-3 proteins in Lewy bodies in Parkinson disease and diffuse Lewy body disease brains". Journal of Neuropathology and Experimental Neurology. 61 (3): 245–253. doi:10.1093/jnen/61.3.245. PMID 11895039.
  23. ^ Dickson DW, Feany MB, Yen SH, Mattiace LA, Davies P (1996). "Cytoskeletal pathology in non-Alzheimer degenerative dementia: New lesions in Diffuse Lewy body disease, Pick's disease, and Corticobasal Degeneration". Journal of Neural Transmission. Supplementum. 47: 31–46. doi:10.1007/978-3-7091-6892-9_2. PMID 8841955.
  24. ^ Popescu A, Lippa CF, Lee VM, Trojanowski JQ (December 2004). "Lewy bodies in the amygdala: increase of alpha-synuclein aggregates in neurodegenerative diseases with tau-based inclusions". Archives of Neurology. 61 (12): 1915–1919. doi:10.1001/archneur.61.12.1915. PMID 15596612.
  25. ^ Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (May 1998). "alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies". Proceedings of the National Academy of Sciences of the United States of America. 95 (11): 6469–6473. Bibcode:1998PNAS...95.6469G. doi:10.1073/pnas.95.11.6469. PMC 27806. PMID 9600990.
  26. ^ Marui W, Iseki E, Kato M, Akatsu H, Kosaka K (August 2004). "Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer's disease". Acta Neuropathologica. 108 (2): 121–128. doi:10.1007/s00401-004-0869-4. PMID 15235805. S2CID 22624886.
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