• Online Features  This Article  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (157)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Topic Collections  • Neurology  • Dementias  • Lewy Body Disease  • Movement Disorders  • Parkinson Disease/ Parkinsonian Disorders  • Alert me on articles by topic  Social Bookmarking   What's this?

Aggregation of Neurofilament and -Synuclein Proteins in Lewy Bodies

Implications for the Pathogenesis of Parkinson Disease and Lewy Body Dementia

John Q. Trojanowski, MD, PhD; Virginia M.-Y. Lee, PhD

Arch Neurol. 1998;55:151-152.

The presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra pars compacta, as well as neuron loss and gliosis, is a diagnostic hallmark of Parkinson disease (PD), but LBs also are seen in other cortical and subcortical neurons of the PD brain.^1-2 Additionally, LBs also occur in similar populations of neurons in the brains of patients with the classic clinical and pathological features of Alzheimer disease (AD).^1-2 Furthermore, the presence of numerous cortical intraneuronal LBs, but only rare AD neurofibrillary tangles and senile plaques in the brains of patients with an AD-like dementia, defines a neurodegenerative disorder known as dementia with LBs (DLB).^1-2 Ultrastructural examination of LBs has revealed masses of aggregated 7- to 25-nm-diameter filaments that appear similar to neurofilaments (NFs), but the precise molecular composition of LBs, including the abnormal filaments in these intracytoplasmic neuronal inclusions, remains to be clarified.^1-2 Indeed, the biological significance of LBs, especially the role that they might play in the degeneration of neurons in LB disorders, is still enigmatic (Figure 1).

View larger version (13K): [in this window] [in a new window] Schematic summary of the spectrum of familial and sporadic Lewy body (LB) disorders that may occur alone or in combination with other diseases, such as Alzheimer disease (AD). Little is known about genetic and environmental risk factors (indicated by the question marks) for Parkinson disease (PD) or dementia with LBs (DLB), but a mutation in the -synuclein gene has been identified in several kindreds with familial PD, and this mutation results in an alanine to threonine substitution at position 53 in the -synuclein protein. Current data suggest that -synuclein and neurofilament (NF) proteins are major constituents of LBs in PD and DLB.

The recent report of a mutation in the -synuclein gene in familial PD³ and the demonstration that -synuclein, but not -synuclein, is a major component of LBs in sporadic PD and DLB⁴ are likely to stimulate increased research on LBs and to prompt a reassessment of the role played by LBs in the pathogenesis of these disorders.^5-6 Since the mutation described in familial PD leads to an alanine to threonine substitution at position 53 (A53T) in the -synuclein protein, this mutation could alter the biophysical properties of -synuclein, a poorly understood protein that is expressed primarily in neurons, where it is localized predominantly at axon terminals or synapses.^5-6 Thus, the A53T mutation in -synuclein could predispose this normally soluble protein to aggregate or interact aberrantly with other proteins (eg, NF subunits), leading to the formation of LBs and the degeneration of affected neurons in familial PD.^{3, 5-6} Moreover, the report of the widespread presence of -synuclein in perikaryal LBs and in dystrophic neuronal processes of sporadic PD and DLB brains⁴ is highly significant for understanding the pathogenesis of these disorders, because this finding implies that wild-type -synuclein may aggregate, alone or with other proteins, into LBs and dystrophic neurites. Nonetheless, it remains to be determined if genetic or epigenetic factors might perturb the metabolism, solubility, or interactions of -synuclein in sporadic PD and synuclein in dystrophic neurites. However, it is plausible that these lesions also could compromise the survival of affected neurons in these nonhereditary LB disorders.

Although insights into the composition of LBs have emerged slowly over the past 15 years, immunohistochemical studies have contributed a substantial amount of indirect information on the proteins found in LBs.^1-2,7 Notably, NF subunits were among the first neuronal proteins detected in the LBs of PD brains,⁷ and epitope-mapping studies of cortical and subcortical LBs in the brains of patients with PD or DLB showed that protein domains spanning nearly the entire extent of each of the 3 NF subunits are present in these inclusions.^8-9 Thus, it is plausible that NFs, the major class of neuronal intermediate filaments, are incorporated into LB filaments.^1-2,7-9 Although antibodies to ubiquitin (Ub) label more LBs than do antibodies to NF subunits, many different brain lesions (eg, neurofibrillary tangles, senile plaques, Rosenthal fibers, Mallory bodies, and Pick bodies) are ubiquitinated.^1-2 The widespead Ub positivity in these lesions may be explained by the fact that Ub is a 76–amino acid protein that is conjugated to other polypeptides through an isopeptide bond between its carboxy terminal glycine and the -amino group of lysine in the target protein.^1-2 Thus, the detection of Ub immunoreactivity in a lesion is not specific for LBs. Although considerable attention has focused on the role of NF proteins and Ub in the pathogenesis of LBs, a large number of other neuronal proteins have been detected in LBs.^1-2 However, many of these proteins may be trapped in LBs in a nonspecific manner, rather than being essential components of LBs.

To gain further insight into the pathology and etiology of LBs, methods for the purification and analysis of these inclusions from the brains of patients with DLB were developed, thereby allowing the generation of monoclonal antibodies to LB proteins.^1-2,10-11 Notably, the findings of these studies have confirmed the presence of NF subunits and Ub in LBs.^1-2,10-11 These and other monoclonal antibodies raised to purified LBs should facilitate efforts to elucidate the biochemical composition of these neuronal inclusions, and this information could be used to determine how LBs form and whether they contribute to the degeneration of affected neurons in PD and DLB. Furthermore, anti-LB monoclonal antibodies could be used to develop assays for the early antemortem diagnosis of LB disorders by monitoring the levels of LB proteins in blood or cerebrospinal fluid. Although information on the biological consequences of LB formation is incomplete, the findings of studies of human LB disorders and transgenic mice in which NF-rich LB-like abnormalities have developed support the notion that these filamentous inclusions could lead to the death of affected neurons.^12-13 However, the refinement and use of methods for the purification and analysis of LBs isolated from postmortem brain tissue should accelerate efforts to dissect the building blocks of the filaments and other components required for the formation of LBs.

Insights into the biological significance of LBs in patients with PD or DLB should emerge more quickly now, as the pace of research on these inclusions accelerates following the discovery that -synuclein is mutated in familial PD and that wild-type -synuclein is a major component of LBs in sporadic PD and DLB. These discoveries will stimulate studies to determine if the aberrant interaction of -synuclein with NFs leads to the abnormal accumulation of these proteins into pathological LBs and whether LBs compromise the function and viability of neurons in PD and DLB brains. Indeed, it is plausible that LBs might have a deleterious effect on neurons in several ways. For example, it is possible that the axons of nigral and cortical neurons might undergo a "dying back" process owing to (1) a disruption of perikaryal transport mechanisms by LBs that form in neuronal cell bodies or (2) a blockage of axonal transport by LB proteins that aggregate in the dystrophic neurites detected by antibodies to -synuclein. The long-term consequences of these pathological events could be the disconnection of the substantia nigra from the striatum and the disconnection of one cortical region from another. Accordingly, efforts to elucidate the pathological significance and the etiology of LBs may to lead to improved strategies for the antemortem diagnosis of LB disorders, as well as to the development of novel therapeutic interventions for the treatment of PD and DLB.

AUTHOR INFORMATION

From the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia.

REFERENCES

Jump to Section  • Top  • Author information  • References

1. Pollanen MS, Dickson SW, Bergeron C. Pathology of the Lewy body. J Neuropathol Exp Neurol. 1993;52:183-191. WEB OF SCIENCE | PUBMED 2. Trojanowski JQ, Galvin JE, Schmidt ML, Tu PH, Iwatsubo T, Lee VM-Y. Mechanisms of neuron death in neurodegenerative diseases of the elderly: role of the Lewy body. In: Wang E, Snyder SD, eds. Handbook of the Aging Brain. Orlando, Fla: Academic Press Inc. In press. 3. Polymeropoulos MH, Lavedan C, Leroy E, et al. -Synuclein gene identified in families with Parkinson's disease. Science. 1997;274:1197-1199. FREE FULL TEXT 4. Spillantini MG, Schmidt ML, Lee VM-Y, Trojanowski JQ, Jakes R, Goedert M. Mutation in the -synuclein in Lewy bodies. Nature. 1997;388:839-840. FULL TEXT | PUBMED 5. Chase TN. A gene for Parkinson disease. Arch Neurol. 1997;54:1156-1157. FREE FULL TEXT 6. Goedert M. The awakening of -synuclein. Nature. 1997;388:232-233. PUBMED 7. Goldman JE, Ye SH, Xhiu FC, Peress NS. Lewy bodies of Parkinson's disease contain neurofilament antigen. Science. 1983;221:1082-1084. FREE FULL TEXT 8. Hill WD, Lee VM-Y, Hurtig HI, Murray JM, Trojanowski JQ. Epitopes located in spatially separate domains of each neurofilament subunit are present in the Lewy bodies of Parkinson's disease. J Comp Neurol. 1991;109:150-160. 9. Schmidt ML, Murray J, Lee VM-Y, Hill DW, Wertkin A, Trojanowski JQ. Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. Am J Pathol. 1991;139:53-65. WEB OF SCIENCE | PUBMED 10. Iwatsubo T, Yamaguchi H, Fujimuro M, et al. Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. Am J Pathol. 1996;148:1517-1529. WEB OF SCIENCE | PUBMED 11. Galvin JE, Lee VM-Y, Baba M, et al. Monoclonal antibodies to purified cortical Lewy bodies recognize the midsize neurofilament subunit. Ann Neurol. 1997;42:595-603. FULL TEXT | WEB OF SCIENCE | PUBMED 12. Tu PH, Robinson KA, de Snoo F, et al. Selective degeneration of Purkinje cells with Lewy body–like inclusions in aged NFHLACZ transgenic mice. J Neurosci. 1997;17:1064-1074. FREE FULL TEXT 13. Tu PH, Gurney ME, Julien JP, Lee VM-Y, Trojanowski JQ. Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease. Lab Invest. 1996;76:1-16.

CiteULike    Connotea    Delicious    Digg    Facebook    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Neuropathological alterations in Alzheimer disease.
Serrano-Pozo et al.
Cold Spring Harb Perspect Med 2011;1:a006189-a006189.
ABSTRACT | FULL TEXT  

Phenylbutyrate Up-regulates the DJ-1 Protein and Protects Neurons in Cell Culture and in Animal Models of Parkinson Disease
Zhou et al.
J. Biol. Chem. 2011;286:14941-14951.
ABSTRACT | FULL TEXT  

The Endoplasmic Reticulum Stress Sensor, ATF6α, Protects against Neurotoxin-induced Dopaminergic Neuronal Death
Egawa et al.
J. Biol. Chem. 2011;286:7947-7957.
ABSTRACT | FULL TEXT  

Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in {alpha}-Synuclein Models of Parkinson's and Lewy Body Diseases
Spencer et al.
J. Neurosci. 2009;29:13578-13588.
ABSTRACT | FULL TEXT  

Bacterial Artificial Chromosome Transgenic Mice Expressing a Truncated Mutant Parkin Exhibit Age-Dependent Hypokinetic Motor Deficits, Dopaminergic Neuron Degeneration, and Accumulation of Proteinase K-Resistant {alpha}-Synuclein
Lu et al.
J. Neurosci. 2009;29:1962-1976.
ABSTRACT | FULL TEXT  

Cellular repair strategies in Parkinson's disease.
Winner et al.
Therapeutic Advances in Neurological Disorders 2009;2:51-60.
ABSTRACT  

{alpha}-Synuclein Alters Notch-1 Expression and Neurogenesis in Mouse Embryonic Stem Cells and in the Hippocampus of Transgenic Mice
Crews et al.
J. Neurosci. 2008;28:4250-4260.
ABSTRACT | FULL TEXT  

Transgenic Mice Overexpressing Tyrosine-to-Cysteine Mutant Human {alpha}-Synuclein: A PROGRESSIVE NEURODEGENERATIVE MODEL OF DIFFUSE LEWY BODY DISEASE
Zhou et al.
J. Biol. Chem. 2008;283:9863-9870.
ABSTRACT | FULL TEXT  

Ubiquitination of {alpha}-synuclein by Siah-1 promotes {alpha}-synuclein aggregation and apoptotic cell death
Lee et al.
Hum Mol Genet 2008;17:906-917.
ABSTRACT | FULL TEXT  

Identification of Novel Proteins Associated with Both {alpha}-Synuclein and DJ-1
Jin et al.
Mol. Cell. Proteomics 2007;6:845-859.
ABSTRACT | FULL TEXT  

{alpha}-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity
Kontopoulos et al.
Hum Mol Genet 2006;15:3012-3023.
ABSTRACT | FULL TEXT  

Combination of 'idiopathic' REM sleep behaviour disorder and olfactory dysfunction as possible indicator for {alpha}-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT
Stiasny-Kolster et al.
Brain 2005;128:126-137.
ABSTRACT | FULL TEXT  

Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models
Perez-Olle et al.
Hum Mol Genet 2004;13:2207-2220.
ABSTRACT | FULL TEXT  

Dementia with Lewy Bodies: Molecular Pathogenesis and Implications for Classification
Cummings
J Geriatr Psychiatry Neurol 2004;17:112-119.
ABSTRACT  

Hsp70 Reduces {alpha}-Synuclein Aggregation and Toxicity
Klucken et al.
J. Biol. Chem. 2004;279:25497-25502.
ABSTRACT | FULL TEXT  

Neurodegeneration in Normal Brain Aging and Disease
Thal et al.
Sci Aging Knowl Environ 2004;2004:pe26-pe26.
ABSTRACT | FULL TEXT  

Does {alpha}-synuclein modulate dopaminergic synaptic content and tone at the synapse?
SIDHU et al.
FASEB J. 2004;18:637-647.
ABSTRACT | FULL TEXT  

Lewy body cortical involvement may not always predict dementia in Parkinson's disease
Colosimo et al.
J. Neurol. Neurosurg. Psychiatry 2003;74:852-856.
ABSTRACT | FULL TEXT  

The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration
Corti et al.
Hum Mol Genet 2003;12:1427-1437.
ABSTRACT | FULL TEXT  

gamma -Synuclein Promotes Cancer Cell Survival and Inhibits Stress- and Chemotherapy Drug-induced Apoptosis by Modulating MAPK Pathways
Pan et al.
J. Biol. Chem. 2002;277:35050-35060.
ABSTRACT | FULL TEXT  

Research Evaluation and Prospective Diagnosis of Dementia With Lewy Bodies
Lopez et al.
Arch Neurol 2002;59:43-46.
ABSTRACT | FULL TEXT  

Attenuated Neurodegenerative Disease Phenotype in Tau Transgenic Mouse Lacking Neurofilaments
Ishihara et al.
J. Neurosci. 2001;21:6026-6035.
ABSTRACT | FULL TEXT  

Direct binding and functional coupling of {alpha}-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis
LEE et al.
FASEB J. 2001;15:916-926.
ABSTRACT | FULL TEXT  

Molecular Etiology of Parkinson Disease: Recent Progress
Shastry
Neuroscientist 2000;6:234-240.
ABSTRACT  

Evidence for Seeding of beta -Amyloid by Intracerebral Infusion of Alzheimer Brain Extracts in beta -Amyloid Precursor Protein-Transgenic Mice
Kane et al.
J. Neurosci. 2000;20:3606-3611.
ABSTRACT | FULL TEXT  

Severity of cognitive impairment and the clinical diagnosis of AD with Lewy bodies
Lopez et al.
Neurology 2000;54:1780-1787.
ABSTRACT | FULL TEXT  

Dopaminergic Loss and Inclusion Body Formation in -Synuclein Mice: Implications for Neurodegenerative Disorders
Masliah et al.
Science 2000;287:1265-1269.
ABSTRACT | FULL TEXT  

Degradation of alpha -Synuclein by Proteasome
Bennett et al.
J. Biol. Chem. 1999;274:33855-33858.
ABSTRACT | FULL TEXT  

Clinical and quantitative pathologic correlates of dementia with Lewy bodies
Gomez-Tortosa et al.
Neurology 1999;53:1284-1284.
ABSTRACT | FULL TEXT  

The G209A Mutation in the {alpha}-Synuclein Gene Is Not Detected in Familial Cases of Parkinson Disease in Non-Greek and/or Italian Populations
Wang et al.
Arch Neurol 1998;55:1521-1523.
ABSTRACT | FULL TEXT  

The Herbicide Paraquat Causes Up-regulation and Aggregation of alpha -Synuclein in Mice. PARAQUAT AND alpha -SYNUCLEIN
Manning-Bog et al.
J. Biol. Chem. 2002;277:1641-1644.
ABSTRACT | FULL TEXT  

alpha -Synuclein Membrane Interactions and Lipid Specificity
Jo et al.
J. Biol. Chem. 2000;275:34328-34334.
ABSTRACT | FULL TEXT