Syndrome Target Tumor Antigen

Subacute cerebellar degeneration Purkinje cells Hodgkin lymphoma Tr

Breast, GYN Yo

SCLC, neuroblastoma Hu

Limbic encephalitis; brainstem encephalitis Various neurons in mesial temporal lobe, brainstem SCLC, neuroblastoma Hu

Testicular, others Ma

Subacute sensory neuropathy Dorsal root ganglion neurons SCLC, neuroblastoma Hu

Opsoclonus myoclonus Unknown (presumed brain stem) Neuroblastoma, Breast Ri

Retinal degeneration Photoreceptors SCLC Recoverin

Stiff-man syndrome Spinal interneurons Breast Amphiphysin

Lambert-Eaton myasthenic syndrome Presynaptic terminals at neuromuscular junction SCLC Presynaptic calcium channel

SCLC, Small cell lung carcinoma.

The major underlying mechanism of these diseases involves the systemic development of an immune response against tumor antigens that can cross-react with antigens in the central or

peripheral nervous systems.[280] [281] The relationship among the underlying malignant process, the clinical features, and the antigens underlying the syndrome are complex. Some tumor

types are associated with multiple types of autoantibodies, and the same antibodies can be present in different clinical syndromes. What allows these antibodies access to the nervous

system and how this immune response to intracellular proteins (for the most part) elicits disease remain unanswered questions. There may also be a component of T cell-mediated

neuronal injury in some settings.[282]

PERIPHERAL NERVE SHEATH TUMORS

These tumors arise from cells of the peripheral nerve, including Schwann cells, perineurial cells, and fibroblasts. Many express Schwann cell characteristics, including the presence of S-

100 antigen as well as the potential for melanocytic differentiation. As nerves exit the brain and spinal cord, there is a transition between myelination by oligodendrocytes and

myelination by Schwann cells. This occurs within several millimeters of the substance of the brain; thus, peripheral nerve tumors can arise within the dura and may cause changes in

adjacent brain or spinal cord. Tumors of comparable histogenesis and biologic behavior also arise along the peripheral course of nerves.

Schwannoma

These benign tumors arise from the neural crest-derived Schwann cell and are associated with neurofibromatosis type 2. Symptoms are referable to local compression of the involved

nerve or to compression of adjacent structures (such as brain stem or spinal cord). Sporadic schwannomas are associated with mutations in the NF2 gene on chromosome 22; there is

usually absence of the NF2 gene product by Western blotting or immunostaining, even if there is no evidence of a mutation in the gene.[283]

Morphology.

Schwannomas are well-circumscribed, encapsulated masses that are attached to the nerve but can be separated from it ( Fig. 28-49A ). Tumors form firm, gray masses but may also have

areas of cystic and xanthomatous change. On microscopic examination, tumors show a mixture of two growth patterns ( Fig. 28-49B ). In the Antoni Apattern of growth, elongated cells

with cytoplasmic processes are arranged in fascicles in areas of moderate to high cellularity with little stromal matrix; the "nuclear-free zones" of processes that lie between the regions

of nuclear palisading are termed Verocay bodies. In the Antoni Bpattern of growth, the tumor is less densely cellular with a loose meshwork of cells along with microcysts and myxoid

changes. In both areas, the cytology of the individual cells is similar, with elongated cell shape and regular oval nuclei. Electron microscopy shows basement membrane deposits

encasing single cells and long-spacing collagen. Because the lesion displaces the nerve of origin as it grows, silver stains or immunostains for neurofilament proteins demonstrate that

axons are largely excluded from the tumor, although they may become entrapped in the capsule. The Schwann cell origin of these tumors is borne out by their S-100 immunoreactivity.

A variety of degenerative changes may be found in schwannomas, including nuclear pleomorphism, xanthomatous change, and vascular hyalinization. Malignant change is extremely

rare in schwannomas, although local recurrence can follow incomplete resection.

Clinical Features.

Within the cranial vault, the most common location of schwannomas is in the cerebellopontine angle, where they are attached to the vestibular branch of the eighth nerve ( Fig. 28-49 ).

Patients often present with tinnitus and hearing loss, and the tumor is often referred to as an acoustic neuroma, although it is more accurately called a vestibular schwannoma. Elsewhere

within the dura, sensory nerves are preferentially involved, including branches of the trigeminal nerve and dorsal roots. When extradural, schwannomas are most commonly found in

association with large nerve trunks, where motor and sensory modalities are intermixed.

Figure 28-49Schwannoma. A, Bilateral eighth nerve schwannomas. (Courtesy of Dr. K.M. Earle.) B, Tumor showing cellular areas (Antoni A), including Verocay bodies (far right), as

well as looser, myxoid regions (Antoni B).

References

1. Gage FH: Mammalian neural stem cells. Science 287:1433, 2000.

2. Graham D, Lantos P (eds): Greenfield's Neuropathology. London, Arnold, 2002.

3. Victor M, Ropper AH, Adams RD: Adams & Victor's Principles of Neurology. New York, McGraw-Hill, 2000.

4. Parent A: Carpenter's Human Neuroanatomy. Baltimore, Williams and Wilkins, 1996.

5. Mountcastle V: The columnar organization of the neocortex. Brain 120:701, 1997.

6. Peters A, Palay S, Webster H: The Fine Structure of the Nervous System: Neurons and Their Supporting Cells. Philadelphia, WB Saunders, 1991.

7. Cáccamo D, Rubinstein L: Tumors: application of immunohistochemical methods. In Garcia J (ed): Neuropathology: The Diagnostic Approach. St. Louis, Mosby, 1997, p 193.

8. Hickey WF: Basic principles of immunological surveillance of the normal central nervous system. Glia 36:118, 2001.

9. Hickey WF, Kimura H: Perivascular microglial cells of the CNS are bone-marrow derived and present antigen in vivo. Science 239:290, 1988.

10. Keane R, Hickey WF (eds): Immunology of the Nervous System. New York, Oxford University Press, 1997.

11. Garcia J, Mena H: Vascular diseases. In Garcia J (ed): Neuropathology: The Diagnostic Approach, St. Louis, Mosby, 1997, p 263.

12. Koliatsos V, Price D, Axotomy as an experimental model of neuronal injury and cell death. Brain Pathol 6:447, 1996.

13. Norenberg M: Astrocyte responses to CNS injury. J Neuropathol Exp Neurol 53:213–220, 1994.

14. Brenner M, et al: Mutations in GFAP, encoding glial fribrillary acidic protein, are associated with Alexander disease. Nat Genet 27:117, 2001.

15. Wakabayashi K, et al, Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180, 1998.

16. Chin S-M, Goldman J: Glial inclusions in CNS degenerative disease. J Neuropathol Exp Neurol 55:499, 1996.

17. Laterra J, Goldstein W: Ventricular organization of cerebrospinal fluid: blood-brain barrier, brain edema, and hydrocephalus. In Kandel ER, Schwartz JH, Jessell TM (eds):

Principles of Neural Science. Elsevier, New York, 2000, p 1288.

18. Yeargin-Allsopp M, Boyle C: Overview: The epidemiology of neurodevelopmental disorders. Ment Retard Dev Disabil Res Rev 8:113, 2002.

19. Kirby R: Co-occurrence of developmental disabilities with birth defects. Ment Retard Dev Disabil Res Rev 8:182, 2002.

20. Norman M, et al: Congenital Malformations of the Brain: Pathological, Embryological, Clinical, Radiological and Genetic Aspects. New York, Oxford University Press. 1995, p 452.

21. Rubenstein J, et al: Regionalization of the prosencephalic neural plate. Annu Rev Neurosci 21:445, 1998.

22. Friede RL: Developmental Neuropathology. Berlin, Springer-Verlag, 1989.

23. Kammermeier L, Reichert H: Common developmental genetic mechanisms for patterning invertebrate and vertebrate brains. Brain Res Bull 55:675, 2001.

24. Trainor P, Krumlauf R: Patterning the cranial neural crest: hindbrain segmentation and Hox gene plasticity. Nat Rev Neurosci 1:116, 2000.

25. Lucock M: Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab 71:121, 2000.

26. Lucock M, et al: An examination of polymorphic genes and folate metabolism in mothers affected by a spina bifida pregnancy. Mol Genet Metab 73:322, 2001.

27. Moyers S, Bailey L: Fetal malformations and folate metabolism: review of recent evidence. Nutr Rev 59:215, 2001.

28. Gelineau-van Waes J, Finnell R: Genetics of neural tube defects. Semin Pediatr Neurol 8:160, 2001.

29. Volcik, K, et al: Testing for genetic associations in a spina bifida population: analysis of the HOX gene family and human candidate gene regions implicated by mouse models of

neural tube defects. Am J Med Genet 110:203, 2002.

30. Dobyns W: Lissencephaly and other genetic disorders of neuronal migration: 1995 update. Neuropediatrics 26:132, 1995.

31. Mizuguchi M, et al: Lissencephaly gene product. Localization in the central nervous system and loss of immunoreactivity in Miller-Dieker syndrome. Am J Pathol 147:1142, 1995.

32. Fairen A, Morante-Oria J, Frassoni C: The surface of the developing cerebral cortex: still special cells one century later. Prog Brain Res 136:281, 2002.

33. Ross ME, Walsh CA: Human brain malformations and their lessons for neuronal migration. Annu Rev Neurosci 24:1041, 2001.

34. Monuki E.S, Walsh CA: Mechanisms of cerebral cortical patterning in mice and humans. Nat Neurosci 4:S1199, 2001.

35. Chenn A, Walsh CA: Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297:365, 2002.

36. Roessler E: Mutations in the human Sonic hedgehog gene cause holoprosencephaly. Nat Genet 14:357, 1996.

37. Cohen MJ, Shiota K: Teratogenesis of holoprosencephaly. Am J Med Genet 109:1, 2002.

38. Volpe J: Neurology of the Newborn. Philadelphia, Saunders, 2001.

39. Kinney H, Armstrong D: Perinatal neuropathology. In Graham D, Lantos P (eds): Greenfield's Neuropathology. London, Arnold, 2002, p 519.

40. Graham D, et al: The nature, distribution and causes of traumatic brain injury. Brain Pathol 5:397, 1995.

41. Leestma J: Forensic neuropathology. In Garcia J (ed): Neuropathology: The Diagnostic Approach. St. Louis, Mosby, 1997, p 475.

42. Povlishock J, Jenkins L: Are the pathobiological changes evoked by traumatic brain injury immediate and irreversible? Brain Pathol 5:415, 1995.

43. Gleckman A, et al: Optic nerve damage in shaken baby syndrome: detection by beta-amyloid precursor protein immunohistochemistry. Arch Pathol Lab Med 124:251, 2000.

44. Stone J, Singleton R, Povlishock JT: Antibodies to the C-terminus of the beta-amyloid precursor protein (APP): a site specific marker for the detection of traumatic axonal injury.

Brain Res 871:288, 2000.

45. Tator C, Koyanagi I: Vascular mechanisms in the pathophysiology of human spinal cord injury. J Neurosurg 86:483, 1997.

46. De Girolami U, Frosch M, Tator C: Regional neuropathology: disease of the spinal cord and vertebral column. In: Graham D, Lantos P (eds): Greenfield's Neuropathology. London,

Arnold, 2002, p 1063.

47. Lo EH, Dalkara T, Moskowitz MA: Mechanisms, challenges, and opportunities in stroke. Nat Rev Neurosci 4:399, 2003.

48. Gladstone DJ, et al: Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33:2123, 2002.

49. Stehbens W, Lie J (eds): Vascular Pathology. London, Chapman & Hall, 1995.

50. Lie J: Classification and histopathologic spectrum of central nervous system vasculitis. Neurol Clin 15:805, 1997.

51. Siva A: Vasculitis of the nervous system. J Neurol 248:451, 2001.

52. Joutel A, et al: Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707 1996.

53. Dichgans M: CADASIL: a monogenic condition causing stroke and subcortical vascular dementia. Cerebrovasc Dis 13:S37, 2002.

54. Karlström H, et al: A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling. Proc Natl Acad Sci U S A

99:17119, 2002.

55. Joutel A, et al: Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differentially affect Jagged 1

binding and Notch 3 activity via the RBP/JK signaling pathway. Am J Human Genet 74:338, 2004.

56. Donahue CP, Kosik KS: Distribution pattern of Notch 3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics 83:59, 2004.

57. Greenberg S: Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment. Neurology 51:690, 1998.

58. O'Donnell H, et al: Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med 342:240, 2000.

59. De Girolami U, Crowell R, Marcoux F: Selective necrosis and total necrosis in focal cerebral ischemia: neuropathologic observations on experimental middle cerebral artery

occlusion in the macaque monkey. J Neuropathol Exp Neurol 43:57, 1984.

60. Garcia J, et al: Ischemic stroke and incomplete infarction. Stroke 27:761, 1996.

61. Gretasdottir S, et al: The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 35:131, 2003.

62. Molinari GF: Lobar hemorrhages: Where do they come from? How did they get there? Stroke 24:523, 1993.

63. Schievink W: Intracranial aneurysms. N Engl J Med 336:28–40, 1997.

64. Winn H, et al: Prevalence of asymptomatic incidental aneurysms: review of 4568 arteriograms. J Neurosurg 96:43, 2002.

65. Juvela S, Porras M, Poussa K: Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. J Neurosurg 93:379, 2000.

66. Sobey C, Faraci F: Subarachnoid haemorrhage: what happens to the cerebral arteries? Clin Exp Pharm Physiol 25:867, 1997.

67. Quan N, Herkenham M, Connecting cytokines and brain: a review of current issues. Histol Histopathol 17:273, 2002.

68. Durand ML, et al: Acute bacterial meningitis in adults: review of 493 episodes. N Engl J Med 328:21, 1993.

69. Gray F: Bacterial infections. Brain Pathol 7:629, 1997.

70. Pong A, Bradley J: Bacterial meningitis and the newborn infant. Infect Dis Clin North Am 13:711, 1999.

71. Choi C: Bacterial meningitis in aging adults. Clin Infect Dis 33:1380, 2001.

72. Booy R, Kroll J: Bacterial meningitis and meningococcal infection. Curr Opin Pediatr 10:13, 1998.

73. Schuchat A, et al: Bacterial meningitis in the United States in 1995. N Engl J Med 337:970, 1997.

74. Quagliarello V, Scheid W: Treatment of bacterial meningitis. N Engl J Med 336:708, 1997.

75. Moris G, Garcia-Monco J: The challenge of drug-induced aseptic meningitis. Arch Int Med 159:1185, 1999.

76. Chun CH, et al: Brain abscess: a study of 45 consecutive cases. Medicine 65:415, 1986.

77. Calfee D, Wispelwey B: Brain abscess. Semin Neurol 20:353, 2000.

78. Thwaites G, et al: Tuberculous meningitis. J Neurol Neurosurg Psychiatry 68:289, 2000.

79. Jellinger K, et al: Neuropathology and general autopsy findings in AIDS during the last 15 years. Acta Neuropathol 100:213, 2000.

80. Garcia-Monco JC, Benach J: Lyme neuroborreliosis. Ann Neurol 37:691, 1995.

81. Logigian EL, Kaplan RF, Steere AC: Chronic neurologic manifestations of Lyme disease. N Engl J Med 323:1438. 1990.

82. Coyle P, Schutzer S: Neurologic aspects of Lyme disease. Med Clinic North Am 86:261–284, 2002.

83. Esiri M: Viruses and rickettsiae. Brain Pathol 7:695, 1997.

84. Redington J, Tyler K: Viral infections of the nervous system, 2002: update on diagnosis and treatment. Arch Neurol 59:712, 2002.

85. Whitley R, Gnann J: Viral encephalitis: familiar infections and emerging pathogens. Lancet 359:507, 2002.

86. Taubenberger J, et al: Initial genetic characterization of the 1918 "Spanish" influenza virus. Science 275:1793. 1997.

87. Roehrig J, et al: The emergence of West Nile virus in North America: ecology, epidemiology, and surveillance. Curr Top Microbiol Immunol 267:223, 2002.

88. Deresiewicz R, et al: Clinical and neuroradiographic manifestation of eastern equine encephalitis. N Engl J Med 336:1867, 1997.

89. Kleinschmidt-DeMasters B, DeBiasi R, Tyler KL: Polymerase chain reaction as a diagnostic adjunct in herpesvirus infections of the nervous system. Brain Pathol 11:452, 2001.

90. Morgello S, et al: Cytomegalovirus encephalitis in patients with acquired immunodeficiency syndrome. Hum Pathol 18:289, 1987.

91. Isaacson S, et al: Cellular localization of poliovirus RNA in the spinal cord during acute paralytic poliomyelitis. Ann N Y Acad Sci 753:194, 1995.

92. Kaminski H, et al: Spinal cord histopathology in long-term survivors of poliomyelitis. Muscle Nerve 18:1208, 1995.

93. Dalakas M: The post-polio syndrome as an evolved clinical entity: definition and clinical description. Ann N Y Acad Sci 753:68, 1995.

94. Noah D, et al: Epidemiology of human rabies in the United States, 1980 to 1996. Ann Internal Med 128:992, 1998.

95. Mrak R, Young L: Rabies encephalitis in humans: pathology, pathogenesis and pathophysiology. J Neuropathol Exp Neurol 53:1, 1994.

96. De Girolami U, et al: Neuropathology of AIDS and pathogenetic considerations. In Worsmer G (ed): AIDS and Other Manifestations of HIV Infection. San Diego, Academic Press,

2004.

97. Hou J, Major E: Progressive multifocal leukoencephalopathy: JC virus induced demyelination in the immune compromised host. J Neurovirol 6 (suppl 2):S98, 2000.

98. Neuenburg JK, et al: HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. J Acquir Immune Defic

Syndr Hum Retrovirol 31:171, 2002.

99. Berger J, et al: Epidemiological evidence and molecular basis of interactions between HIV and JC virus. J Neurovirol 7:329, 2001.

100. Sabath B, Major E: Traffic of JC virus from sites of initial infection to the brain: the path to progressive multifocal leukoencephalopathy. J Infect Dis 186:S180, 2002.

101. Allen I, et al: The significance of measles virus antigen and genome distribution in the CNS in SSPE for mechanisms of viral spread and demyelination. J Neuropathol Exp Neurol

55:471, 1996.

102. Chimelli L, Mahler-Araújo B: Fungal infections. Brain Pathol 7:613, 1997.

103. Porter SB, Sande MA: Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Eng J Med 327:1643, 1992.

104. Martinez A, Visvesvara G: Free-living, amphizoic and opportunistic amebas. Brain Pathol 7:583, 1997.

105. Prusiner SB: Shattuck lecture: neurodegenerative diseases and prions. N Engl J Med 344:1516, 2001.

106. Jackson GS, Collinge J: The molecular pathology of CJD: old and new variants. Mol Pathol 54:393, 2001.

107. Montrasio F, et al: Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288:1257, 2000.

108. Goldfarb L, et al: Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science 258:806, 1992.

109. Parchi P, et al: Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224, 1999.

110. Will R, et al: A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 374:921, 1996.

111. Ironside J: Pathology of variant Creutzfeldt-Jakob disease. Arch Virol Suppl 143, 2000.

112. Hill A, et al: The same prion strain causes vCJD and BSE. Nature 389:448, 1997.

113. Bruce M, et al: Transmissions to mice indicate that 'new variant' CJD is caused by the BSE agent. Nature 389:498, 1997.

114. Prusiner S: Prion diseases and the BSE crisis. Science 278:245, 1997.

115. Foster P: Prions and blood products. Ann Med 32:501, 2000.

116. Valleron A, et al: Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom. Science 294:1726, 2001.

117. Huillard d'Aignaux J, Cousens S, Smith P: Predictability of the UK variant Creutzfeldt-Jakob disease epidemic. Science 294:1729, 2001.

118. Gambetti P, et al: Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features. Brain Pathol 5:43, 1995.

119. Mastrianni J, et al: Prion protein conformation in a patient with sporadic fatal insomnia. N Engl J Med 340:1630, 1999.

120. Sadovnick A: The genetics of multiple sclerosis. Clin Neurol Neurosurg 104:199, 2002.

121. Dyment, D, et al: Genetic susceptibility to MS: a second stage analysis in Canadian MS families. Neurogenetics 3:145, 2001.

122. O'Connor K, Bar-Or A, Hafler D: The neuroimmunology of multiple sclerosis: possible roles of T and B lymphocytes in immunopathogenesis. J Clin Immunol 21:81, 2001.

123. Wingerchuk DM, Lucchinetti CF, Noseworthy JH: Multiple sclerosis: current pathophysiological concepts. Lab Invest 81:263, 2001.

124. Martin R, et al: Molecular mimicry and antigen-specific T cell responses in multiple sclerosis and chronic CNS Lyme disease. J Autoimmun 16:187, 2001.

125. Baranzini SE, Oksenberg JR, Hauser SL: New insights into the genetics of multiple sclerosis. J Rehabil Res Dev 39:201, 2002.

126. Steinman L, et al: Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu Rev Neurosci 25:491, 2002.

127. Lucchinetti C, et al: Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol 6:259, 1996.

128. Lucchinetti C, et al: Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707, 2000.

129. Wingerchuk D, Lucchinetti C, Noseworthy J: Multiple sclerosis: current pathophysiological concepts. Lab Invest 81:263, 2001.

130. Kleinschmidt-DeMasters BK, Norenberg MD Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis. Science 211:1068, 1981.

131. Lampl C, Yazdi K: Central pontine myelinolysis. Eur Neurol 47:3, 2002.

132. Brown W: Osmotic demyelination disorders: central pontine and extrapontine myelinolysis. Curr Opin Neurol 13:691, 2001.

133. Dickson DW: Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, 2003.

134. Evans DA, et al: Prevalence of Alzheimer's disease in a community population of older persons: higher than previously reported. JAMA 262:2551, 1989.

135. Gao S, et al: The relationships between age, sex, and the incidence of dementia and alzheimer disease: a meta-analysis. Arch Gen Psychiatry 55:809, 1998.

136. von Strauss E, et al: Aging and the occurrence of dementia: findings from a population-based cohort with a large sample of nonagenarians. Arch Neurol 56:587, 1999.

137. Cummings J, Cole G: Alzheimer disease. JAMA 287:2335, 2002.

138. Braak H, Braak E: Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351, 1997.

139. Braak H, Braak E: Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl) 82:239, 1991.

140. Mirra S, et al: The consortium to establish a registry for Alzheimer's disease (CERAD). Part II: standardization of the neuropathologic assessment of Alzheimer's disease.

Neurology 41:479, 1991.

141. Mirra SM, Hart MN, Terry RD: Making the diagnosis of Alzheimer's disease. Arch Pathol Lab Med 117:131, 1993.

142. National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease: Consensus recommendations

for the postmortem diagnosis of Alzheimer's disease. Neurobiol Aging 18:S1, 1997.

143. Thal D, et al: Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791, 2002.

144. Lemere C, et al: Sequence of deposition of heterogeneous amyloid beta-peptides and Apo E in Down syndrome: implications for initial events in amyloid plaque formation.

Neurobiol Dis 3:16, 1996.

145. Iwatsubo T, et al: Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43).

Neuron 13:45, 1994.

146. Iwatsubo T, et al: Amyloid beta protein (Abeta) deposition: Abeta42(43) precedes Abeta40 in Down syndrome. Ann Neurol 37:294, 1995.

147. Mumm J, Kopan R: Notch signaling: from the outside in. Dev Biol 228:151, 2000.

148. Selkoe D: Presenilin, Notch, and the genesis and treatment of Alzheimer's disease. Proc Natl Acad Sci U S A 98:11039, 2001.

149. Selkoe D: Alzheimer's disease: genes, proteins, and therapy. Phys Rev 81:741, 2001.

150. Strittmatter W, et al: Apolipoprotein E: high avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U

S A 90:1977, 1993.

References

151. Blacker D, et al: Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 19:357, 1998.

152. Bertram L, et al: Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science 290:2302, 2000.

153. Zandi PJ, Breitner J: Do NSAIDs prevent Alzheimer's disease? And, if so, why? The epidemiological evidence. Neurobiol Aging 22:811, 2001.

154. McGeer P, McGeer E: Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging 22:799, 2001.

155. in t' Veld B, et al: Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 345:1515, 2001.

156. Weggen S, et al: A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414:212, 2001.

157. Killiany R, et al: Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease. Ann Neurol 47:430, 2000.

158. Yoshiyama Y, Lee V-Y, Trojanowski J: Frontotemporal dementia and tauopathy. Curr Neurol Neurosci Rep 1:413, 2001.

159. McKann G, et al: Clinical and pathological diagnosis of frontotemporal dementia: Report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch Neurol

58:1803, 2001.

160. Buee L, et al: Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Rev 33:95, 2000.

161. Lee V.-Y, Goedert M, Trojanowski J: Neurodegenerative tauopathies. Ann Rev Neurosci 24:1121, 2001.

162. Dickson D: Neuropathology of Pick's disease. Neurology 56 (suppl 4):S16, 2001.

163. Baker M, et al: Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8:711, 1999.

164. Feany M, Dickson D: Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am J Pathol 146:1388, 1995.

165. Feany M, Mattiace L, Dickson D: Neuropathologic overlap of progressive supranuclear palsy, Pick's disease and corticobasal degeneration. J Neuropathol Exp Neurol 55:53, 1996.

166. Dickson D, et al: Cytoskeletal pathology in non-Alzheimer degenerative dementia: new lesions in diffuse Lewy body disease, Pick's disease, and corticobasal degeneration. J Neural

Transm Suppl 47:31, 1996.

167. Dickson DW, et al: Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61:935, 2002.

168. Rebeiz J, Kolodny E, Richardson EJ: Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 18:20, 1968.

169. Schneider J, et al: Corticobasal degeneration: neuropathologic and clinical heterogeneity. Neurology 48:959, 1997.

170. Di Maria E, et al: Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol 47:374, 2000.

171. Mirra S, et al: Tau pathology in a family with dementia and a P301L mutation in tau. J Neuropath Exp Neurol 58:335, 1999.

172. Knopman D, et al: Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia. Neurology 40:251, 1990.

173. Vinters H, et al: Neuopathologic substrates of ischemic vascular dementia. J Neuropath Exp Neurol 59:931, 2000.

174. Snowdon D, et al: Brain infarction and the clinical expression of Alzheimer disease: the nun study. JAMA 277:813, 1997.

175. Schlossmacher M, et al: Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Am J Pathol 160:1655, 2002.

176. Bergman H, Deuschl G: Pathophysiology of Parkinson's disease: from clinical neurology to basic neuroscience and back. Mov Disord 17:S28, 2002.

177. Le Couteur D, et al: Pesticides and Parkinson's disease. Biomed Pharmacother 53:122–130, 1999.

178. Chen J, et al: Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J Neurosci 21:RC143, 2001.

179. Ross G, Petrovitch H: Current evidence for neuroprotective effects of nicotine and caffeine against Parkinson's disease. Drugs Aging 18:797, 2001.

180. Tanner C, et al: Smoking and Parkinson's disease in twins. Neurology 58:581, 2002.

181. Goedert M: Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2:492, 2001.

182. Lotharius J, et al: Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J Biol Chem 277:38884, 2002.

183. Polymeropoulos M.H., et al: Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276:2045, 1997.

184. Kruger R, et al: Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 18:106, 1988.

185. Zarranz JJ, et al: The new mutation, E46K, of a-synuclein causes Parkinson and Levy body dementia. Ann Neurol 55:164, 2004.

186. Singleton AB, et al: a-synuclein locus triplication causes Parkinson's disease. Science 302:841, 2003.

187. Farrer M, et al: Comparison of kindreds with parkinsonism and a-synuclein genomic multiplications. Ann Neurol 55:174, 2004.

188. Kitada T, et al: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605, 1988.

189. Lucking C.B, et al: Association between early-onset Parkinson's disease and mutations in the parkin gene: French Parkinson's Disease Genetics Study Group. New Engl J Med

342:1560, 2000.

190. Hayashi S, et al: An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene. Mov Disord 15:884, 2000.

191. van de Warrenburg BP, et al: Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 56:555, 2001.

192. Farrer M, et al: Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol 50:293, 2001.

193. Shimura H, et al: Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293:263, 2001.

194. Leroy E, et al: The ubiquitin pathway in Parkinson's disease. Nature 395:451, 1998.

195. Liu Y, et al: The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 111:209, 2002.

196. Bonifati V, et al: Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:526, 2003.

197. Bonifati V, Oostra BA, Heutink P: Linking DJ-1 to neurodegeneration offers novel insights for understanding the pathogenesis of Parkinson's disease. J Mol Med Jan 8, 2004 (epub

ahead of print).

198. Bandopadhyay R, et al: The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease. Brain 127:420, 2004.

199. McKeith I, et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.

Neurology 47:1113, 1996.

200. Freed C, et al: Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 344:710, 2001.

201. Lozano A, Lang A: Pallidotomy for Parkinson's disease. Adv Neurol 86:413, 2001.

202. Olanow C, Brin M, Obeso J: The role of deep brain stimulation as a surgical treatment for Parkinson's disease. Neurology 55:S60, 2000.

203. Papp M, Kahn J, Lantos P: Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy, Shy-Drager

syndrome). J Neurol Sci 94:79, 1989.

204. Burn J, Jaros E: Multiple system atrophy: cellular and molecular pathology. Mol Pathol 54:419, 2001.

205. Duda J, Lee V-Y, Trojanowski J: Neuropathology of synuclein aggregates: new insights into mechanisms of neurodegenerative diseases. J Neurosci Res 61:121, 2000.

206. Spillantini M, et al: Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett 251:205, 1988.

207. Cairns N, et al: Tau protein in the glial cytoplasmic inclusions of multiple system atrophy can be distinguished from abnormal tau in Alzheimer's disease. Neurosci Lett 230:49,

1997.

208. Papp M, Lantos P: The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 271:235, 1994.

209. Richardson E: Huntington's disease: some recent neuropathological studies. Neuropathol Appl Neurobiol 16:451, 1990.

210. The Huntington's Disease Collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell

72:971, 1993.

211. Snell R, et al: Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet 4:393, 1993.

212. Davies S, Ramsden D: Huntington's disease. Mol Pathol 54:409, 2001.

213. DiFiglia M, et al: Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990, 1997.

214. Nucifora FJ, et al: Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291:2423, 2001.

215. Dunah A, et al: Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science 296:2238, 2002.

216. Klockgether T, et al: The molecular biology of the autosomal-dominant cerebellar ataxias. Mov Dis 15:604, 2000.

217. Perlman S: Spinocerebellar degenerations: an update. Curr Neurol Neurosci Rep 2:331, 2002.

218. Campuzano V, et al: Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271:1423, 1996.

219. Babcock M, et al: Regulation of mitochondrial iron accumulation by Yfh1p, a putative homology of frataxin. Science 276:1709, 1997.

220. Branda S, et al: Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase. J Biol Chem 274:22763, 1999.

221. Shiloh Y: ATM (ataxia telangiectasia mutated): expanding roles in the DNA damage response and cellular homeostasis. Biochem Soc Trans 29:661, 2001.

222. Rotman G, Shiloh Y: ATM: from gene to function. Hum Mol Genet 7:1555, 1998.

223. Mitsumoto H, Chad D, Pioro E: Amyotrophic Lateral Sclerosis. Philadelphia, FA Davis, 1998.

224. Hand C, Rouleau G: Familial amyotrophic lateral sclerosis. Muscle Nerve 25:135, 2002.

225. Rosen D, et al: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59, 1993.

226. Cudkowicz M, et al: Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol 41:210, 1997.

227. Cudkowicz M, et al: Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc superoxide dismutase gene. Ann

Neurol 43:703, 1998.

228. Yang Y, et al: The gene encoding alsin, a protein with three guaninenucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet

29:160, 2001.

229. Hadano S, et al: A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 29:166, 2001.

230. Li M, et al: Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 44:249, 1998.

231. Amato A, et al: Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology 43:791, 1993.

232. Wenger D, et al: Krabbe disease: genetic aspects and progress towards therapy. Molec Gen Metab 70:1, 2000.

233. Koeppen AH, Robitaille Y: Pelizaeus-Merzbacher disease. J Neuropathol Exp Neurol 61:747, 2002.

234. Sistermans E, et al: Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology 50:1749, 1998.

235. Kaul R, et al: Cloning of the human aspartoacylase cDNA and a common mutation in Canavan disease. Nat Genet 5:118, 1993.

236. Leonard J, Schapira A: Mitochondrial respiratory chain disorders Part I: mitochondrial DNA defects. Lancet 355:299, 2000.

237. Leonard J, Schapira A: Mitochondrial respiratory chain disorders. Part II: neurodegenerative disorders and nuclear gene defects. Lancet 355:389, 2000.

238. Tanji K, et al: Neuropathological features of mitochondrial disorders. Semin Cell Dev Biol 12:429, 2001.

239. Di Donato S: Disorders related to mitochondrial membranes: pathology of the respiratory chain and neurodegeneration. J Inherit Metab Dis 23:247, 2000.

240. DiMauro S, Servidei S, Zeviani M: Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol 22:498, 1987.

241. Tiranti V, Jaksch M, Hofmann S: Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency. Ann Neurol

46:161, 1999.

242. Tatuch Y, et al: Heteroplasmic mtDNA mutation (TÕG) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 50:852, 1992.

243. Tanji K, et al: Cytochrome c oxidase deficiency in the microvasculature of MELAS-3243 brains. Ann Neurol 44:458, 1998.

244. Zeviani M, et al: Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 38:1339, 1988.

245. Schultheiss T, et al: Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 31:1093, 1995.

246. Russell DS, Rubinstein LJ: Pathology of Tumors of the Nervous System. Baltimore, Williams & Wilkins, 1989.

247. Kleihues P, Cavanee W (eds): Pathology and Genetics of Tumours of the Nervous System: World Health Organization Classification of Tumors. Lyon, France, IARC Press, 2000.

248. Burger P, Scheithauer B, Vogel F: Surgical Pathology of the Nervous System and its Coverings. New York, Churchill Livingstone, 2002.

249. Lantos P, et al: Tumours of the nervous system. In Graham D, Lantos P (eds): Greenfield's Neuropathology. London, Arnold, 2002, p 767.

250. Ironside J, et al: Diagnostic Pathology of Nervous System Tumours. London, Churchill Livingstone, 2002.

251. Bigner D, McLendon R, Bruner J (eds): Russell and Rubinstein's Pathology of Tumors of the Nervous System. Arnold, London, 1998.

252. Kleihues P, et al: The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215, 2002.

253. Louis D: A molecular genetic model of astrocytoma histopathology. Brain Pathol 7:755, 1997.

254. von Deimling A, et al: Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol 3:19–26. 1997.

255. Watanabe K, et al: Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6:217,

1996.

256. Kleihues P, Ohgaki H: Primary and secondary glioblastoma: from concept to clinical diagnosis. Neuro-oncol 1:44, 1999.

257. Burger P, et al: Small cell architecture: a histological equivalent of EGFR amplification in glioblastoma multiforme? J Neuropathol Exp Neurol 60:1099, 2001.

258. Giannini C, et al: Pleomorphic xanthoastrocytoma: what do we really know about it? Cancer 85:2033, 1999.

259. Freeman C, Farmer J: Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys 40:265, 1998.

260. Guillamo J-S, et al: Brainstem gliomas in adults: prognostic factors and classification. Brain 124:2528, 2001.

261. Cairncross J, et al: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473, 1998.

262. Ino Y, et al: Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis. Clin Cancer Res 7:839, 2001.

263. Reifenberger J, et al: Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145:1175, 1994.

264. Maintz D, et al: Molecular genetic evidence for subtypes of oligoastrocytomas. J Neuropathol Exp Neurol 56:1098, 1997.

265. Ueki K, et al: Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors. Clin

Cancer Res 8:196, 2002.

266. Ebert C, et al: Molecular genetic analysis of ependymal tumors. NF2 mutations and chromosome 22q loss occur preferentially in intramedullary spinal ependymomas. Am J Pathol

155:627, 1999.

267. Komori T, et al: Papillary glioneuronal tumor: a new variant of mixed neuronal-glial neoplasm. Am J Surg Pathol 22:1171, 1998.

268. Stanescu Cosson R, et al: Dysembryoplastic neuroepithelial tumors: CT, MR findings and imaging follow-up: a study of 53 cases. J Neuroradiol 28:230, 2001.

269. Daumas-Duport C, et al: Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases.

Neurosurgery 23:545, 1988.

270. Segal R, et al: Expression of the neurotrophin receptor TRKC is linked to a favorable outcome in medulloblastoma. Proc Natl Acad Sci U S A 91:12867, 1994.

271. Pomeroy S, et al: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415:436, 2002.

272. Rorke L, Packer R, Biegel J: Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg 85:56 1996.

273. Biegel J, et al: Narrowing the critical region for a rhabdoid tumor locus in 22q11. Genes Chromosomes Cancer 16:94, 1996.

274. Biegel J, et al: Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59:74, 1999.

275. Uno K, et al: Aberrations of the hSNF5/INI1 gene are restricted to malignant rhabdoid tumors or atypical teratoid/rhabdoid tumors in pediatric solid tumors. Genes Chromosomes

Cancer 34:33, 2002.

276. Hao D, et al: Is primary CNS lymphoma really becoming more common?: a population-based study of incidence, clinicopathological features and outcomes in Alberta from 1975 to

1996. Ann Oncol 10:65, 1999.

277. Corn B, et al: Will primary central nervous system lymphoma be the most frequent brain tumor diagnosed in the year 2000? Cancer 79:2409, 1997.

278. Wellenreuther R, et al: Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. Am J Pathol 146:827, 1995.

279. Rosenfeld M, Dalmau J: The clinical spectrum and pathogenesis of paraneoplastic disorders of the central nervous system. Hematol Oncol Clin North Am 15:1109, 2001.

280. Rudnicki S, Dalmau J: Paraneoplastic syndromes of the spinal cord, nerve, and muscle. Muscle Nerve 23:1800, 2000.

281. Posner J, Dalmau J: Paraneoplastic syndromes of the nervous system. Clin Chem Lab Med 38:117, 2000.

282. Voltz R, et al: T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis. Neurology 51:1146, 1998.

283. Huynh D, et al: Immunohistochemical detection of schwannomin and neurofibromin in vestibular schwannomas, ependymomas and meningiomas. J Neuropathol Exp Neurol

56:382, 1997.

284. Serra E, et al: Confirmation of the double-hit model for the NF1 gene in benign neurofibromas. Am J Hum Genet 61:512, 1997.

285. Neilsen G, et al: Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation. Am J Pathol 155:1879, 1999.

286. Birindelli S, et al: Rb and TP53 pathway alterations in sporadic and NF1-related malignant peripheral nerve sheath tumors. Lab Invest 81:833, 2001.

287. North K: Neurofibromatosis type 1. Am J Med Genet 97:119, 2000.

288. Korf B: Diagnosis and management of neurofibromatosis type 1. Curr Neurol Neurosci Rep 1:162, 2001.

289. Gusella J, et al: Merlin: the neurofibromatosis 2 tumor suppressor. Biochim Biophys Acta 142:M29, 1999.

290. Bretscher A, Edwards K, Fehon R: ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 3:586, 2002.

291. Merel P, et al: Screening for germ-line mutations in the NF2 gene. Genes Chromosomes Cancer 12:117, 1995.

292. van Slegtenhorst M, et al: Identification of the tuberous sclerosis gene TSC1 in chromosome 9q34. Science 277:805, 1997.

293. The European Chromosome 16 Tuberous Sclerosis Consortium: identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305, 1993.

294. Plank T, Yeung R, Henske E: Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res

58:4766, 1998.

295. Cheadle J, et al: Molecular genetic advances in tuberous sclerosis. Hum Genet 107:97, 2000.

296. Hengstschlager M, et al: Tuberous sclerosis gene products in proliferation control. Mutat Res 488:233, 2001.

297. Johnson M, et al: Co-localization of TSC1 and TSC2 gene products in tubers of patients with tuberous sclerosis. Brain Pathol 9:45, 1999.

298. Iwai K, et al: Identification of the von Hippel-Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A 96:12436, 1999.

299. Maxwell PH, et al: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271, 1999.

300. Pause A, et al: The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci U S A 95:993, 1998.

Date: 2016-04-22; view: 565