Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17

Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17

^aDepartment of Neurology and Gallo Clinic and Research Center, University of California, San Francisco, CA 94110; ^cVeterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA 98108; ^dDivision of Gerontology and Geriatric Medicine, Department of Medicine, and Departments of ^lNeurology and ^mPharmacology, University of Washington, Seattle, WA 98108; ^eDepartment of Internal Medicine, Neurology Section, University of Nebraska Medical Center, Omaha, NE 68198; ^fDepartment of Neurology, Program in Neurogenetics, Reed Neurological Research Center, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095; ^gUniversité de Sherbrooke, Service de Neurologie, Hôpital Charles LeMoyne, Greenfield Park, Québec, Canada J1H 5N4; ^hDepartment of Neurology, Oregon Health Sciences University, Portland, OR 97201; ⁱFaculty of Medicine, Department of Human Genetics, Universiteit Amsterdam, Amsterdam, The Netherlands 1081BT; ^jE. K. Shriver Center, Department of Biomedical Sciences, Waltham, MA 02254; and ^kDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104

Edited by Ira Herskowitz, University of California, San Francisco, CA, and approved August 21, 1998 (received for review June 5, 1998)

Abstract

Pallido-ponto-nigral degeneration (PPND) is one of the most well characterized familial neurodegenerative disorders linked to chromosome 17q21–22. These hereditary disorders are known collectively as frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17). Although the clinical features and associated regional variations in the neuronal loss observed in different FTDP-17 kindreds are diverse, the diagnostic lesions of FTDP-17 brains are tau-rich filaments in the cytoplasm of specific subpopulations of neurons and glial cells. The microtubule associated protein (tau) gene is located on chromosome 17q21–22. For these reasons, we investigated the possibility that PPND and other FTDP-17 syndromes might be caused by mutations in the tau gene. Two missense mutations in exon 10 of the tau gene that segregate with disease, ^Asn279^Lys in the PPND kindred and ^Pro301^Leu in four other FTDP-17 kindreds, were found. A third mutation was found in the intron adjacent to the 3′ splice site of exon 10 in patients from another FTDP-17 family. Transcripts that contain exon 10 encode tau isoforms with four microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with three MT-binding repeats (3Rtau). The insoluble tau aggregates isolated from brains of patients with each mutation were analyzed by immunoblotting using tau-specific antibodies. For each of three mutations, abnormal tau with an apparent M_r of 64 and 69 was observed. The dephosphorylated material comigrated with tau isoforms containing exon 10 having four MT-binding repeats but not with 3Rtau. Thus, the brains of patients with both the missense mutations and the splice junction mutation contain aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration.

frontotemporal dementia and Parkinsonism/tauopathies/glial and neuronal tangles/microtubule associated proteins/Alzheimer’s disease

Footnotes

↵ b L.N.C., P.P., G.S., and K.C.W. contributed equally to this work.
↵ n To whom reprint requests should be addressed at: Gallo Clinic and Research Center, University of California, San Francisco, Building 1, Room 101, 1001 Potrero Avenue, San Francisco, CA 94110. e-mail: kcw1{at}itsa.ucsf.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
ABBREVIATIONS:

FTD,

frontotemporal dementia;

FTDP,

FTD and parkinsonism;

DDPAC,

disinhibition–dementia–parkinsonism–amyotrophy complex;

PPND,

pallido-ponto-nigral degeneration;

MT,

microtubule;

AD,

Alzheimer’s disease;

PHF,

paired helical filament