A Closer Look at Lewy Bodies

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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

Lewy Bodies and Neurites

Lewy bodies (round brown/black structures) and Lewy neurites (brown/black strands) in the substantia nigra of a person with Parkinson’s disease.
Image courtesy of Suraj Rajan / CC BY-SA (https://creativecommons.org/ licenses/ by-sa/3.0)

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 

Alpha Synuclein Aggregation

Alpha synuclein is shown at the top right bound to a membrane. It dissociates to form unfolded monomers in the cytosol, which can be induced to aggregate into oligomers, fibrils, and eventually Lewy bodies. Adapted from Cookson, 200910; Mark R Cookson / CC BY (https://creativecommons.org/licenses/by/2.0)

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.

Do Neurons Die in Parkinson’s Disease Because They Lack Trophic Support?

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Lipids are in the news again, with a recently published hypothesis proposing that age-dependent decreases in GM1 ganglioside can trigger Parkinson’s disease.(1) Forsayeth and Hadaczek describe parkinsonian-like neurodegeneration in humans and animals with mutations in ganglioside metabolic pathways. In their view, the age-related loss of GM1 prevents glial cell derived neurotrophic factor (GDNF) from signaling and, without this trophic support, selected catecholaminergic neurons die.

Neuronal membrane showing the insertion of gangliosides (labeled as glycolipids) and other functional molecules

Gangliosides are lipids that consist of carbohydrates with a 9-carbon backbone and a carboxylic acid group. They are primarily located in the plasma membranes of nerve cells, where they are involved in cell-cell recognition, adhesion and, importantly for this new hypothesis, signal transduction.(2)  Under physiological conditions, they can form lipid rafts–specialized microdomains in neuronal membranes that help cells perform a host of important functions such as assembly of signaling molecules, concentration of protein receptors, and regulation of intracellular signaling. The graphic above doesn’t show the close association of proteins, carbohydrates, and gangliosides that constitute lipid rafts, but a good graphic can be found in this article.

Forsayeth and Hadaczek describe findings with the B4GALNT1 knockout mouse, which lacks an enzyme involved in the synthesis of GM1 ganglioside. Mice without this enzyme show progressive motor deficits with age, loss of neurons in the substantia nigra, and accumulation of alpha synuclein in the substantia nigra. Administration of LIGA20, a brain-permeable GM1 ganglioside analog, can ameliorate these pathological features.(3)

The proposed mechanism by which reduction or loss of GM1 ganglioside involves GDNF. Forsayeth and Hadaczek believe that locally released GDNF acts in the striatum and possibly other areas to upregulate presynaptic dopaminergic function in response to selected molecular cues. GDNF binding and signaling depends on lipid rafts and, without enough functional GM1 ganglioside, lipid rafts can’t function properly, GDNF cannot exert its trophic effects, and neurons die.(1)

The alpha synuclein accumulation that characterizes Parkinson’s disease is also explained in this hypothesis. Alpha synuclein binds gangliosides, and forms fibrils in the absence of GM1 ganglioside.(4) Alpha synuclein aggregates can be eliminated in the B4GALNT knockout mouse model with overexpression of GDNF in the striatum, which also eliminates the motor deficits shown in this model.(5) The authors suggest that alpha synuclein enables the delivery of GM1 ganglioside to lipid rafts, which are needed for the trophic action of GDNF.

In this hypothesis, the loss of GM1 ganglioside is only one possible route to trophic failure of catecholaminergic neurons and, ultimately, Parkinson’s disease. One can envision other mechanisms that could interfere with GDNF signaling, from reduced release of dense core vesicles (the mechanism proposed by the authors for GDNF release), to GDNF receptor dysfunction, to interference with intracellular signaling mechanisms and pathways. This interesting hypothesis adds to the growing literature implicating lipids in Parkinson’s disease; for a summary of how Parkinson’s disease genes are linked to lipids, see the blog post below left.

Transplanted Cells in Parkinson’s Disease Continue to Inform

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It’s been nearly a decade since groups in the United States1 and Sweden2 reported alpha synuclein pathology in transplanted cells grafted into the brains of people with Parkinson’s disease. The Lewy body-like inclusions were accompanied by other markers of neuronal dysfunction that apparently developed over 10+ years. The pathology is remarkable because the transplanted cells were young and genetically unrelated to the individuals with Parkinson’s disease, suggesting an ongoing degenerative process in the parkinsonian brain and the presence of a pathological microenvironment.3

The finding of Lewy-like inclusions in transplanted cells led to the hypothesis that Parkinson’s disease could be a type of prion disease, involving  the cell to cell transfer of misfolded alpha synuclein.2 Similarities between prion diseases and Parkinson’s disease had been documented in the literature since the early 1990s, but no pathology was observed in the prion protein involved in Creutzfeldt-Jakob’s disease.4 The observation of similarities persisted, though, and led to the concept of permissive templating–a process thought to be common to Parkinson’s, Creutzfeldt-Jakob’s, Alzheimer’s, Huntington’s, and other diseases of protein aggregation.5

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Parkinson’s Disease Genes Linked to Lipids

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There’s no shortage of genes associated with Parkinson’s disease.

Known mutations in 6 genes can cause early onset or classical, late onset Parkinson’s disease, and mutations in at least 2 more can cause atypical parkinsonian syndromes.1 Additional genetic loci and identified genes increase the susceptibility to Parkinson’s disease.

Although the identified genes are not all part of the same biological pathway, identifying commonalities among them may provide clues to the disease process.  One theme that emerges from these studies is the involvement of lipids.2 Investigators have identified links between Parkinson’s disease and lipids for at least 20 years.3 Lipids are integral to biological membranes, such as those that encase nerve cells and cellular organelles, and are a major component of gangliosides, a type of glycolipid concentrated in plasma membranes that participates in cell-cell recognition, adhesion, and signal transduction.4 Below is a list of genes associated with Parkinson’s disease that encode proteins with lipid-related functions.

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On the Trail of Olfactory Deficits in Parkinson’s Disease

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A friend told me that his father could never smell cookies or coffee—a seemingly harmless idiosyncrasy that was frequently the subject of family jokes. No one had any idea that the olfactory deficits could be linked to Parkinson’s disease, and everyone was surprised by the diagnosis when motor symptoms appeared years later.

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From Glucocerebrosidase to Autophagy and Mitophagy in Parkinson’s Disease

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Over the past two decades, researchers have documented numerous links between Parkinson’s disease and Gaucher disease. Rare patients with Gaucher disease show parkinsonian symptoms1 and many more have family members with Parkinson’s disease.2 Lewy bodies—large aggregates of alpha synuclein protein characteristic of Parkinson’s disease—have been identified in the brains of Gaucher patients,3 and approximately 5-10% of those with sporadic Parkinson’s disease show mutations in the glucocerebrosidase gene, the cause of Gaucher disease.4,5

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Following the Pathway Analysis in Parkinson’s Disease

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Pathway analyses of genomic data make intuitive sense to me for conditions like Parkinson’s disease. Only a handful of single genes have been consistently associated with Parkinson’s, but the genomic picture is certainly larger, and we are faced with the complex possibility that numerous rarer variations play a role. The underlying assumption of pathway analyses is that diverse genomic variations may be part of common pathways that, when dysfunctional, may lead to disease.

pathway-small

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Rationale for Nilotinib and Other Kinase Inhibitors in Parkinson’s Disease

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For many months, those who follow Parkinson’s disease clinical research have been anticipating the results of a small study of the cancer drug nilotinib. The study, now published in Journal of Parkinson’s Disease,1 suggests that nilotinib and perhaps other

Nilotinib molecule ball and stick model

Nilotinib molecule,  ball and stick model

kinase inhibitors are worthy of more serious attention as treatments for Parkinson’s and related diseases. The “related diseases” part is important here because 5 of the 12 study participants were diagnosed with dementia with Lewy bodies.

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Synaptic Dysfunction in Parkinson’s Disease: The Chicken or the Egg?

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Figuring out what happens first in Parkinson’s disease is a difficult Chicken egg pixabay (2)task. People are not usually diagnosed until they experience motor symptoms, at which point 70-80% of their nigrostriatal dopamine neurons have already died. This makes it hard to trace the sequence of events that leads to neuronal degeneration.

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Why Don’t We All Get Parkinson’s Disease?

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This seems like an odd question given that only a small percentage of people actually get Parkinson’s disease. Nevertheless, the question has always perplexed me.

sagittal-brain-pixabay-cropped
Here’s my rationale. The main neurons responsible for the motor
symptoms of Parkinson’s disease are dopamine-containing cells that project from the substantia nigra pars compacta to the striatum. In the striatum, each nigrostriatal dopamine neuron branches into a dizzying array of tiny appendages that make hundreds of thousands of synapses.1, 2 And these neurons do not merely send the occasional message. They are pacemakers, constantly firing at a slow, steady rate, hour after hour, year after year. Can you imagine how much energy it takes to constantly transport cargo to hundreds of thousands of branches? How many mitochondria these cells need to produce adequate energy? Recycle vesicles? Make new neurotransmitter? Get rid of old proteins and organelles? You’d think the nigrostriatal dopamine neurons would simply wear out in all of our brains.

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