A large Indiana kindred is affected by an autosomal dominant neurologic disorder. The disease of the Indiana kindred is characterized clinically by cerebral ataxia, parkinsonism and dementia, and pathologically by amyloid plaques, neuritic plaques, neurofibrillary tangles (as in Alzheimer disease), nerve-cell loss and presence of iron deposits in the striatum and substantia nigra. Abnormal eye movements are present early in the disease and may precede onset of neurologic signs. Amyloid of plaques is not recognized by polyclonal antibodies against the Alzheimer disease beta- protein, but does contain epitopes recognized by antibodies against a prion protein (PrP). However, unlike PrP-positive cases of Gerstmann-Straussler- Scheinker syndrome, in which there are mutations in the open reading frame (ORF) of the PrP gene, no putative disease-causing mutation has been found in the PrP ORF of the Indiana kindred. We postulate that the disease of the Indiana kindred is a distinct entity that shares clinical and pathologic similarities with Gerstmann-Straussler-Scheinker syndrome on the one hand and with Alzheimer disease on the other. Our overall goal is to expand and correlate information on several aspects of the Indiana kindred, each relevant to a Program Project to be developed within the next three years. We propose to: (I) Conduct prospective clinical and brain magnetic resonance imaging to clarify the natural history of the disease; (II) Define the ocular motor functions in at-risk and affected subjects; (III) Continue defining the pathology of the Indiana kindred; (IV) Biochemically characterize the amyloid of the Indiana kindred and (V) Determine the chromosomal map position of the disease-causing gene. The study of this neurodegenerative process will contribute to the understanding of the basic mechanisms operating in central nervous system amyloidogenesis and neurofibrillary tangle formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029822-03
Application #
2267934
Study Section
Pathology A Study Section (PTHA)
Project Start
1991-07-01
Project End
1994-11-30
Budget Start
1993-07-01
Budget End
1994-11-30
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Monaco, Salvatore; Fiorini, Michele; Farinazzo, Alessia et al. (2012) Allelic origin of protease-sensitive and protease-resistant prion protein isoforms in Gerstmann-Sträussler-Scheinker disease with the P102L mutation. PLoS One 7:e32382
Gambetti, Pierluigi; Kong, Qingzhong; Zou, Wenquan et al. (2003) Sporadic and familial CJD: classification and characterisation. Br Med Bull 66:213-39
Piccardo, P; Liepnieks, J J; William, A et al. (2001) Prion proteins with different conformations accumulate in Gerstmann-Straussler-Scheinker disease caused by A117V and F198S mutations. Am J Pathol 158:2201-7
Tagliavini, F; Lievens, P M; Tranchant, C et al. (2001) A 7-kDa prion protein (PrP) fragment, an integral component of the PrP region required for infectivity, is the major amyloid protein in Gerstmann-Straussler-Scheinker disease A117V. J Biol Chem 276:6009-15
Piccardo, P; Dlouhy, S R; Lievens, P M et al. (1998) Phenotypic variability of Gerstmann-Straussler-Scheinker disease is associated with prion protein heterogeneity. J Neuropathol Exp Neurol 57:979-88
Jimenez-Huete, A; Lievens, P M; Vidal, R et al. (1998) Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues. Am J Pathol 153:1561-72
Piccardo, P; Langeveld, J P; Hill, A F et al. (1998) An antibody raised against a conserved sequence of the prion protein recognizes pathological isoforms in human and animal prion diseases, including Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Am J Pathol 152:1415-20
Spillantini, M G; Bird, T D; Ghetti, B (1998) Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol 8:387-402
Spillantini, M G; Goedert, M; Crowther, R A et al. (1997) Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci U S A 94:4113-8
Young, K; Clark, H B; Piccardo, P et al. (1997) Gerstmann-Straussler-Scheinker disease with the PRNP P102L mutation and valine at codon 129. Brain Res Mol Brain Res 44:147-50

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