Since the early 1900s, Lewy bodies have been a primary distinguishing feature of Parkinson’s disease pathology. First described by Dr. Friederich Lewy in 1912, Lewy bodies appear under light microscopes as large sphere-shaped masses in neuronal cell bodies and are accompanied by spindle-like inclusions in neuronal process referred to as Lewy neurites.¹ In addition to aggregated alpha synuclein and ubiquitin, Lewy bodies contain at least 90 other molecules.²

Everyone agrees that Lewy bodies and neurites are not the hallmarks of happy, healthy neurons. But experts disagree on whether they drive neurodegeneration or whether they represent a cell’s attempt to save itself.² The hypothesis implicating Lewy bodies in neurodegeneration begins with the formation of alpha synuclein oligomers, which may be initiated following uptake of alpha synuclein aggregates from the extracellular space in a prion-like manner.³ The oligomers then form beta-sheet-rich amyloid fibrils and eventually Lewy bodies and neurites. In support of this view, Lewy bodies and neurites are commonly observed in brain regions that degenerate in Parkinson’s disease and their sequential appearance in these regions is the basis of a well-established pathologic staging system.⁴ 

However, Lewy pathology is not always found in the brains of people with Parkinson’s disease. Individuals with certain mutations, including the PRKN gene and certain LRRK2 variants, develop Parkinson’s disease without Lewy bodies and neurites.^5,6,7,8 Moreover, Lewy pathology is observed in the brains of approximately a quarter of elderly individuals without parkinsonian symptoms.⁹ Thus, the nature of the link between Lewy bodies and neurodegeneration in Parkinson’s disease is still unclear.

A recent study by Shahmoradian and colleagues using correlative light and electron microscopy provides a more detailed, nanoscale look at Lewy body and neurite composition than has been possible in the past,¹¹ leading to some surprising findings. Instead of comprising primarily fibrillar alpha synuclein as previously thought, Lewy bodies and neurites were found to contain crowded membranous material, including fragmented organelles such as mitochondria and lysosomes, as well as lipids, nonfibrillar alpha synuclein, and disrupted cytoskeletal elements. Fibrillar alpha synuclein was still detected, but only in a minority of Lewy bodies and neurites. Among the many visually striking photos in the Shahmoradian article is a circular Lewy body with mitochondria ringing the entire outside, alpha synuclein staining the outer third, and lysosomes both clustered around the outside and staining an inner ring (see Figure 7 of Shahmoradian et al.).¹¹

These results likely have important implications for understanding Parkinson’s disease pathology. The authors concluded that their observations point to altered organellar trafficking as a potential disease mechanism.  As explained by Bartels in a companion editorial,¹² the interactions between membrane-bound alpha synuclein and trafficking vesicles may be disrupted in Parkinson’s disease, causing vesicles to cluster abnormally. These clusters may eventually become insoluble, at which time they are detected as Lewy bodies. Evidence from animal studies raises the possibility that the lipid-rich Lewy bodies represent the early stage of pathology, whereas amyloid fibril formation may represent late stage pathology.¹³

So, what do these findings mean for Parkinson’s disease research? Should we focus more on alpha synuclein’s interactions with lipids and/or membranes? Do people with Parkinson’s disease who don’t show traditional Lewy bodies using methods that detect fibrillar alpha synuclein nevertheless show the membrane-rich clusters found by Shahmoradian et al.? Like any good study, this one has raised a plethora of new questions.

References
1.   Braak H, de Vos RA, Jansen EN, Bratzke H, Braak E. Neuropathological hallmarks of Alzheimer’s and Parkinson’s diseases. Prog Brain Res. 1998;117:267-85.
2.    Wakabayashi K, Tanji K, Odagiri S, Miki Y, Mori F, Takahashi H. The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol Neurobiol. 2013;47(2):495-508.
3. Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008;14(5):501-3.
4.  Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004;318(1):121-34.
5. Doherty KM, Hardy J. Parkin disease and the Lewy body conundrum. Mov Disord. 2013;28(6):702-4.
6. Doherty KM, Silveira-Moriyama L, Parkkinen L, Healy DG, Farrell M, Mencacci NE, et al. Parkin disease: a clinicopathologic entity? JAMA Neurol. 2013;70(5):571-9.
7. Marti-Masso JF, Ruiz-Martinez J, Bolano MJ, Ruiz I, Gorostidi A, Moreno F, et al. Neuropathology of Parkinson’s disease with the R1441G mutation in LRRK2. Mov Disord. 2009;24(13):1998-2001.
8. Vilas D, Gelpi E, Aldecoa I, Grau O, Rodriguez-Diehl R, Jauma S, et al. Lack of central and peripheral nervous system synuclein pathology in R1441G LRRK2-associated Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2019;90(7):832-3.
9. Markesbery WR, Jicha GA, Liu H, Schmitt FA. Lewy body pathology in normal elderly subjects. J Neuropathol Exp Neurol. 2009;68(7):816-22.
10. Cookson MR. alpha-Synuclein and neuronal cell death. Mol Neurodegener. 2009;4:9.
11. Shahmoradian SH, Lewis AJ, Genoud C, Hench J, Moors TE, Navarro PP, et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nat Neurosci. 2019;22(7):1099-109.
12. Bartels T. A traffic jam leads to Lewy bodies. Nat Neurosci. 2019;22(7):1043-5.
13. Nuber S, Rajsombath M, Minakaki G, Winkler J, Muller CP, Ericsson M, et al. Abrogating Native alpha-synuclein tetramers in mice causes a L-DOPA-responsive motor syndrome closely resembling Parkinson’s disease. Neuron. 2018;100(1):75-90 e5.