Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia

The abnormal aggregation of proteins into fibrillar lesions is a neuropathological hallmark of several sporadic and hereditary neurodegenerative diseases. For example, Lewy bodies (LBs) are intracytoplasmic filamentous inclusions that accumulate primarily in subcortical neurons of patients with Parkinson's disease (PD), or predominantly in neocortical neurons in a subtype of Alzheimer's disease (AD) known as the LB variant of AD (LBVAD) and in dementia with LBs (DLB). Aggregated neurofilament subunits and α-synuclein are major protein components of LBs, and these inclusions may contribute mechanistically to the degeneration of neurons in PD, DLB and LBVAD. Here we review recent studies of the protein building blocks of LBs, as well as the role LBs play in the onset and progression of PD, DLB and LBVAD. Increased understanding of the protein composition and pathological significance of LBs may provide insight into mechanisms of neuron dysfunction and death in other neurodegenerative disorders characterized by brain lesions containing massive deposits of proteinacious fibrils.

[1]  J Q Trojanowski,et al.  Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. , 1998, The American journal of pathology.

[2]  A. Hackam,et al.  Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates , 1998, Nature Genetics.

[3]  J. Trojanowski,et al.  Epitopes located in spatially separate domains of each neurofilament subunit are present in parkinson's disease lewy bodies , 1991, The Journal of comparative neurology.

[4]  R. Crowther,et al.  α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies , 1998 .

[5]  A. Roses,et al.  The human NACP/alpha-synuclein gene: chromosome assignment to 4q21.3-q22 and TaqI RFLP analysis. , 1995, Genomics.

[6]  Michel Goedert,et al.  Identification of two distinct synucleins from human brain , 1994, FEBS letters.

[7]  Michel Goedert,et al.  Familial Parkinson's disease: The awakening of α-synuclein , 1997, Nature.

[8]  John A. Martin,et al.  Convergence of Lewy bodies and neurofibrillary tangles in amygdala neurons of Alzheimer’s disease and Lewy body disorders , 1996, Acta Neuropathologica.

[9]  John Q Trojanowski,et al.  Polyglutamine-containing aggregates in neuronal intranuclear inclusion disease , 1998, The Lancet.

[10]  J. Goldman,et al.  Lewy bodies of Parkinson's disease contain neurofilament antigens. , 1983, Science.

[11]  S. Tsuji,et al.  Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch , 1998, Nature Genetics.

[12]  L. Hansen,et al.  Criteria for Alzheimer's Disease and the Nosology of Dementia with Lewy Bodies , 1997, Neurology.

[13]  B. Hyman,et al.  Characterization of the Precursor Protein of the Non-Aβ Component of Senile Plaques (NACP) in the Human Central Nervous System , 1996, Journal of neuropathology and experimental neurology.

[14]  E. Masliah,et al.  Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[15]  D. Galasko,et al.  Neocortical Lewy Body Counts Correlate with Dementia in the Lewy Body Variant of Alzheimer's Disease , 1996, Journal of neuropathology and experimental neurology.

[16]  T. Aiuchi,et al.  Purification and Characterization of a Novel Brain‐Specific 14‐kDa Protein , 1990, Journal of neurochemistry.

[17]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[18]  R A Crowther,et al.  Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  P. Lansbury,et al.  NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. , 1996, Biochemistry.

[20]  T. Chase.  A gene for Parkinson disease. , 1997, Archives of neurology.

[21]  W. Honer,et al.  Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. , 1998, The American journal of pathology.

[22]  G. Schellenberg,et al.  Tau is a candidate gene for chromosome 17 frontotemporal dementia , 1998, Annals of neurology.

[23]  M. Goedert.  The Neurofibrillary Pathology of Alzheimer's Disease , 1997 .

[24]  H. Zoghbi,et al.  α-synuclein—a link between Parkinson and Alzheimer diseases? , 1997, Nature Genetics.

[25]  Akihiko Iwai,et al.  The precursor protein of non-Aβ component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system , 1995, Neuron.

[26]  M S Pollanen,et al.  Detergent‐Insoluble Cortical Lewy Body Fibrils Share Epitopes with Neurofilament and τ , 1992, Journal of neurochemistry.

[27]  J Q Trojanowski,et al.  Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. , 1991, The American journal of pathology.

[28]  M. L. Schmidt,et al.  α-Synuclein in Lewy bodies , 1997, Nature.

[29]  R. Scheller,et al.  Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[30]  J. Trojanowski,et al.  Mechanisms of Neuron Death in Neurodegenerative Diseases of the Elderly , 1998 .

[31]  C. Bergeron,et al.  Deposition of detergent-resistant neurofilaments into Lewy body fibrils , 1993, Brain Research.

[32]  J Q Trojanowski,et al.  Selective Degeneration of Purkinje Cells with Lewy Body-Like Inclusions in Aged NFHLACZ Transgenic Mice , 1997, The Journal of Neuroscience.

[33]  M. Gurney,et al.  Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[34]  E. Zamrini,et al.  Apoptotic-like changes in Lewy-body-associated disorders and normal aging in substantia nigral neurons. , 1997, The American journal of pathology.

[35]  J Q Trojanowski,et al.  Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. , 1998, The American journal of pathology.

[36]  D. Dickson,et al.  Pathology and Biology of the Lewy Body , 1993, Journal of neuropathology and experimental neurology.

[37]  J. Wood,et al.  Peripheral Nervous System-specific Genes Identified by Subtractive cDNA Cloning (*) , 1995, The Journal of Biological Chemistry.

[38]  D. Dickson,et al.  Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease , 1991, Neurology.

[39]  S. Nakajo,et al.  Cell and tissue distribution and developmental change of neuron specific 14 kDa protein (phosphoneuroprotein 14) , 1993, Brain Research.

[40]  M. Yoshimoto,et al.  NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. Nakajo,et al.  Distribution of phosphoneuroprotein 14 (PNP 14) in vertebrates: its levels as determined by enzyme immunoassay , 1996, Brain Research.

[42]  R. Scheller,et al.  The rat brain synucleins; family of proteins transiently associated with neuronal membrane. , 1991, Brain research. Molecular brain research.

[43]  R. Heilig,et al.  The NACP/synuclein gene: chromosomal assignment and screening for alterations in Alzheimer disease. , 1995, Genomics.

[44]  K. Kosaka,et al.  Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB) , 1996, Neurology.

[45]  Junying Yuan,et al.  ICE, neuronal apoptosis and neurodegeneration , 1998, Cell Death and Differentiation.

[46]  P. Lansbury.  Structural Neurology: Are Seeds at the Root of Neuronal Degeneration? , 1997, Neuron.

[47]  B. Hyman,et al.  Nigral and Cortical Lewy Bodies and Dystrophic Nigral Neurites in Parkinson's Disease and Cortical Lewy Body Disease Contain α-synuclein Immunoreactivity , 1998, Journal of neuropathology and experimental neurology.

[48]  J Q Trojanowski,et al.  Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α‐synuclein , 1998, Annals of neurology.

[49]  S. Nakajo,et al.  A new brain-specific 14-kDa protein is a phosphoprotein. Its complete amino acid sequence and evidence for phosphorylation. , 1993, European journal of biochemistry.

[50]  M. Goedert,et al.  Assignment of human alpha-synuclein (SNCA) and beta-synuclein (SNCB) genes to chromosomes 4q21 and 5q35. , 1995, Genomics.

[51]  Hitoshi Takahashi,et al.  NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson's disease , 1997, Neuroscience Letters.

[52]  G. Xiao,et al.  Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. , 1997, Cancer research.

[53]  G. Withers,et al.  Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. , 1997, Brain research. Developmental brain research.

[54]  J. Trojanowski,et al.  Monoclonal antibodies to purified cortical lewy bodies recognize the mid‐size neurofilament subunit , 1997, Annals of neurology.

[55]  R. Sadoul.  BCL-2 family members in the development and degenerative pathologies of the nervous system , 1998, Cell Death and Differentiation.

[56]  David F. Clayton,et al.  Characterization of a novel protein regulated during the critical period for song learning in the zebra finch , 1995, Neuron.