TY - JOUR
T1 - CNS cell type-specific gene profiling of P301S tau transgenic mice identifies genes dysregulated by progressive tau accumulation
T2 - RNA profiling in P301S tau transgenic mice
AU - Ke, Yazi D.
AU - Chan, Gabriella
AU - Stefanoska, Kristie
AU - Au, Carol
AU - Bi, Mian
AU - Müller, Julius
AU - Przybyla, Magdalena
AU - Feiten, Astrid
AU - Prikas, Emmanuel
AU - Halliday, Glenda M.
AU - Piguet, Olivier
AU - Kiernan, Matthew C.
AU - Kassiou, Michael
AU - Hodges, John R.
AU - Loy, Clement T.
AU - Mattick, John S.
AU - Ittner, Arne
AU - Kril, Jillian J.
AU - Sutherland, Greg T.
AU - Ittner, Lars M.
PY - 2019/9/20
Y1 - 2019/9/20
N2 - The microtubule-associated protein tau undergoes aberrant modification resulting in insoluble brain deposits in various neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal degeneration. Tau aggregates can form in different cell types of the central nervous system (CNS) but are most prevalent in neurons. Wehave previously recapitulated aspects of humanFTDin mouse models by overexpressing mutant human tau in CNS neurons, including a P301S tau variant in TAU58/2 mice, characterized by early-onset and progressive behavioral deficits and FTD-like neuropathology. The molecular mechanisms underlying the functional deficits of TAU58/2 mice remain mostly elusive. Here, we employed functional genomics (i.e. RNAseq) to determine differentially expressed genes in young and aged TAU58/2 mice to identify alterations in cellular processes that may contribute to neuropathy. We identified genes in cortical brain samples differentially regulated between young and old TAU58/2 mice relative to nontransgenic littermates and by comparative analysis with a dataset of CNS cell type-specific genes expressed in nontransgenic mice. Most differentiallyregulated genes had known or putative roles in neurons and included presynaptic and excitatory genes. Specifically, we observed changes in presynaptic factors, glutamatergic signaling, and protein scaffolding. Moreover, in the aged mice, expression levels of several genes whose expression was annotated to occur in other brain cell types were altered. Immunoblotting and immunostaining of brain samples from the TAU58/2 mice confirmed altered expression and localization of identified and network-linked proteins. Our results have revealed genes dysregulated by progressive tau accumulation in an FTD mouse model.
AB - The microtubule-associated protein tau undergoes aberrant modification resulting in insoluble brain deposits in various neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal degeneration. Tau aggregates can form in different cell types of the central nervous system (CNS) but are most prevalent in neurons. Wehave previously recapitulated aspects of humanFTDin mouse models by overexpressing mutant human tau in CNS neurons, including a P301S tau variant in TAU58/2 mice, characterized by early-onset and progressive behavioral deficits and FTD-like neuropathology. The molecular mechanisms underlying the functional deficits of TAU58/2 mice remain mostly elusive. Here, we employed functional genomics (i.e. RNAseq) to determine differentially expressed genes in young and aged TAU58/2 mice to identify alterations in cellular processes that may contribute to neuropathy. We identified genes in cortical brain samples differentially regulated between young and old TAU58/2 mice relative to nontransgenic littermates and by comparative analysis with a dataset of CNS cell type-specific genes expressed in nontransgenic mice. Most differentiallyregulated genes had known or putative roles in neurons and included presynaptic and excitatory genes. Specifically, we observed changes in presynaptic factors, glutamatergic signaling, and protein scaffolding. Moreover, in the aged mice, expression levels of several genes whose expression was annotated to occur in other brain cell types were altered. Immunoblotting and immunostaining of brain samples from the TAU58/2 mice confirmed altered expression and localization of identified and network-linked proteins. Our results have revealed genes dysregulated by progressive tau accumulation in an FTD mouse model.
KW - Tau protein (Tau)
KW - Neurodegenerative disease
KW - Mouse
KW - Gene expression
KW - Neurobiology
KW - Transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=85072517474&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1081916
UR - http://purl.org/au-research/grants/NHMRC/1103258
UR - http://purl.org/au-research/grants/NHMRC/1107657
UR - http://purl.org/au-research/grants/NHMRC/1132524
UR - http://purl.org/au-research/grants/NHMRC/1136241
UR - http://purl.org/au-research/grants/NHMRC/1143848
UR - http://purl.org/au-research/grants/NHMRC/1143978
UR - http://purl.org/au-research/grants/ARC/DP170100781
UR - http://purl.org/au-research/grants/ARC/DP170100843
UR - http://purl.org/au-research/grants/ARC/CE110001021
U2 - 10.1074/jbc.RA118.005263
DO - 10.1074/jbc.RA118.005263
M3 - Article
C2 - 31366728
AN - SCOPUS:85072517474
VL - 294
SP - 14149
EP - 14162
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 1083-351X
IS - 38
ER -