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Neurological Review |

Aggregation of Neurofilament and α-Synuclein Proteins in Lewy Bodies:  Implications for the Pathogenesis of Parkinson Disease and Lewy Body Dementia FREE

John Q. Trojanowski, MD, PhD; Virginia M.-Y. Lee, PhD
[+] Author Affiliations

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


Arch Neurol. 1998;55(2):151-152. doi:10.1001/archneur.55.2.151.
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Published online

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).

Place holder to copy figure label and caption

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 α-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 α-synuclein protein. Current data suggest that α-synuclein and neurofilament (NF) proteins are major constituents of LBs in PD and DLB.

Graphic Jump Location

The recent report of a mutation in the α-synuclein gene in familial PD3 and the demonstration that α-synuclein, but not β-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 α-synuclein protein, this mutation could alter the biophysical properties of α-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 α-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 α-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 α-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 α-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.1,2,79 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 ϵ-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 α-synuclein is mutated in familial PD and that wild-type α-synuclein is a major component of LBs in sporadic PD and DLB. These discoveries will stimulate studies to determine if the aberrant interaction of α-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 α-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.

ARTICLE INFORMATION

Accepted for publication November 13, 1997.

This study was supported in part by grants AG09215, AG10124, and NS-18616 from the National Institute on Aging, National Institutes of Health, Bethesda, Md.

Reprints: John Q. Trojanowski, MD, PhD, or Virginia M.-Y. Lee, PhD, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney Building, Third Floor, Philadelphia, PA 19104-4283.

Pollanen  MSDickson  SWBergeron  C Pathology of the Lewy body. J Neuropathol Exp Neurol. 1993;52183- 191
Link to Article
Trojanowski  JQGalvin  JESchmidt  MLTu  PHIwatsubo  TLee  VM-Y Mechanisms of neuron death in neurodegenerative diseases of the elderly: role of the Lewy body. Wang  ESnyder  SDeds.Handbook of the Aging Brain. Orlando, Fla Academic Press IncIn press.
Polymeropoulos  MHLavedan  CLeroy  E  et al.  α-Synuclein gene identified in families with Parkinson's disease. Science. 1997;2741197- 1199
Link to Article
Spillantini  MGSchmidt  MLLee  VM-YTrojanowski  JQJakes  RGoedert  M Mutation in the α-synuclein in Lewy bodies. Nature. 1997;388839- 840
Link to Article
Chase  TN A gene for Parkinson disease. Arch Neurol. 1997;541156- 1157
Link to Article
Goedert  M The awakening of α-synuclein. Nature. 1997;388232- 233
Link to Article
Goldman  JEYe  SHXhiu  FCPeress  NS Lewy bodies of Parkinson's disease contain neurofilament antigen. Science. 1983;2211082- 1084
Link to Article
Hill  WDLee  VM-YHurtig  HIMurray  JMTrojanowski  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;109150- 160
Link to Article
Schmidt  MLMurray  JLee  VM-YHill  DWWertkin  ATrojanowski  JQ Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. Am J Pathol. 1991;13953- 65
Iwatsubo  TYamaguchi  HFujimuro  M  et al.  Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. Am J Pathol. 1996;1481517- 1529
Galvin  JELee  VM-YBaba  M  et al.  Monoclonal antibodies to purified cortical Lewy bodies recognize the midsize neurofilament subunit. Ann Neurol. 1997;42595- 603
Link to Article
Tu  PHRobinson  KAde Snoo  F  et al.  Selective degeneration of Purkinje cells with Lewy body–like inclusions in aged NFHLACZ transgenic mice. J Neurosci. 1997;171064- 1074
Tu  PHGurney  MEJulien  JPLee  VM-YTrojanowski  JQ Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease. Lab Invest. 1996;761- 16

Figures

Place holder to copy figure label and caption

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 α-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 α-synuclein protein. Current data suggest that α-synuclein and neurofilament (NF) proteins are major constituents of LBs in PD and DLB.

Graphic Jump Location

Tables

References

Pollanen  MSDickson  SWBergeron  C Pathology of the Lewy body. J Neuropathol Exp Neurol. 1993;52183- 191
Link to Article
Trojanowski  JQGalvin  JESchmidt  MLTu  PHIwatsubo  TLee  VM-Y Mechanisms of neuron death in neurodegenerative diseases of the elderly: role of the Lewy body. Wang  ESnyder  SDeds.Handbook of the Aging Brain. Orlando, Fla Academic Press IncIn press.
Polymeropoulos  MHLavedan  CLeroy  E  et al.  α-Synuclein gene identified in families with Parkinson's disease. Science. 1997;2741197- 1199
Link to Article
Spillantini  MGSchmidt  MLLee  VM-YTrojanowski  JQJakes  RGoedert  M Mutation in the α-synuclein in Lewy bodies. Nature. 1997;388839- 840
Link to Article
Chase  TN A gene for Parkinson disease. Arch Neurol. 1997;541156- 1157
Link to Article
Goedert  M The awakening of α-synuclein. Nature. 1997;388232- 233
Link to Article
Goldman  JEYe  SHXhiu  FCPeress  NS Lewy bodies of Parkinson's disease contain neurofilament antigen. Science. 1983;2211082- 1084
Link to Article
Hill  WDLee  VM-YHurtig  HIMurray  JMTrojanowski  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;109150- 160
Link to Article
Schmidt  MLMurray  JLee  VM-YHill  DWWertkin  ATrojanowski  JQ Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. Am J Pathol. 1991;13953- 65
Iwatsubo  TYamaguchi  HFujimuro  M  et al.  Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. Am J Pathol. 1996;1481517- 1529
Galvin  JELee  VM-YBaba  M  et al.  Monoclonal antibodies to purified cortical Lewy bodies recognize the midsize neurofilament subunit. Ann Neurol. 1997;42595- 603
Link to Article
Tu  PHRobinson  KAde Snoo  F  et al.  Selective degeneration of Purkinje cells with Lewy body–like inclusions in aged NFHLACZ transgenic mice. J Neurosci. 1997;171064- 1074
Tu  PHGurney  MEJulien  JPLee  VM-YTrojanowski  JQ Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease. Lab Invest. 1996;761- 16

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