Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17.
Tau proteins aggregate as cytoplasmic inclusions in a number of neurodegenerative diseases, including Alzheimer's disease and hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Over 10 exonic and intronic mutations in the tau gene have been identified in about 20 FTDP-17 families. Analyses of soluble and insoluble tau proteins from brains of FTDP-17 patients indicated that different pathogenic mutations differentially altered distinct biochemical properties and stoichiometry of brain tau isoforms. Functional assays of recombinant tau proteins with different FTDP-17 missense mutations implicated all but one of these mutations in disease pathogenesis by reducing the ability of tau to bind microtubules and promote microtubule assembly.
Hong
M
M
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Zhukareva
V
V
Vogelsberg-Ragaglia
V
V
Wszolek
Z
Z
Reed
L
L
Miller
B I
BI
Geschwind
D H
DH
Bird
T D
TD
McKeel
D
D
Goate
A
A
Morris
J C
JC
Wilhelmsen
K C
KC
Schellenberg
G D
GD
Trojanowski
J Q
JQ
Lee
V M
VM
D017398:Alternative Splicing; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17; D003704:Dementia / Q000235:genetics* / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation; D020125:Mutation, Missense; D010302:Parkinson Disease, Secondary / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D013577:Syndrome; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D020033:Protein Isoforms; D011994:Recombinant Proteins; D016875:tau Proteins