Abstract
Frontotemporal lobar degeneration (FTLD) has been subdivided based on the main pathology found in the brains of affected individuals. When the primary pathology is aggregated, hyperphosphorylated tau, the pathological diagnosis is FTLD-tau. When the primary pathology is cytoplasmic and/or nuclear aggregates of phosphorylated TAR-DNA-binding protein (TDP-43), the pathological diagnosis is FTLD-TDP. Notably, TDP-43 pathology can also occur in conjunction with a number of neurodegenerative disorders; however, unknown environmental and genetic factors may regulate this TDP-43 pathology. Using transgenic mouse models of several diseases of the central nervous system, we explored whether a primary proteinopathy might secondarily drive TDP-43 proteinopathy. We found abnormal, cytoplasmic accumulation of phosphorylated TDP-43 specifically in two tau transgenic models, but TDP-43 pathology was absent in mouse models of Aβ deposition, α-synucleinopathy or Huntington’s disease. Though tau pathology showed considerable overlap with cytoplasmic, phosphorylated TDP-43, tau pathology generally preceded TDP-43 pathology. Biochemical analysis confirmed the presence of TDP-43 abnormalities in the tau mice, which showed increased levels of high molecular weight, soluble TDP-43 and insoluble full-length and ~35 kD TDP-43. These data demonstrate that the neurodegenerative cascade associated with a primary tauopathy in tau transgenic mice can also promote TDP-43 abnormalities. These findings provide the first in vivo models to understand how TDP-43 pathology may arise as a secondary consequence of a primary proteinopathy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1123-8) contains supplementary material, which is available to authorized users.
Highlights
The major classes of frontotemporal lobar degeneration (FTLD) are those characterized by the presence of neuronalW.-L
TAR DNA-binding protein of 43 kDa (TDP-43) aggregation, cytoplasmic redistribution, phosphorylation and misprocessing characterize the pathology found in FTLD-TDP, associated with mutations in the GRN, Valosin Containing Protein (VCP), and C9ORF72 genes [3, 10, 54]
Bieniek et al [4] reported tau pathology in brains of individuals with FTLD associated with the C9ORF72 expansion mutation, but similar elevation of tauopathy were not observed in FTLD associated with GRN mutations suggesting that an overlap of FTLDTDP and FTLD-Tau may occur in the context of C9ORF72
Summary
The major classes of frontotemporal lobar degeneration (FTLD) are those characterized by the presence of neuronal. Familial forms of FTLD-tau are associated with mutations in the MAPT gene that encodes the tau protein, whilst mutations in Granulin (GRN), Valosin Containing Protein (VCP), or C9ORF72 genes can cause FTLD-TDP or amyotrophic lateral sclerosis [3, 10, 22, 54] Neurodegenerative conditions such as Alzheimer’s disease (AD), Huntington disease (HD), as well as Parkinson disease (PD) and dementia with Lewy bodies (DLB) are proposed to be “secondary” TDP-43 proteinopathies in which TDP-43 pathology occurs in the context of the distinctive hallmark pathology of each of these disorders [1, 21, 37, 47, 51]. We sought to address the possible association between TDP-43 aggregation and other proteinopathies through the neuropathological analysis of mouse models of amyloidosis, tauopathy, α-synucleinopathy, and HD This approach attempts to isolate the effect of each model’s defining genetic trigger and proteinopathy on TDP-43 aggregation, thereby eliminating parallel mechanisms that may cause TDP-43 pathology in humans (i.e., unrelated genetic or environmental factors). We demonstrate that tau-driven mechanisms can drive abnormal TDP-43 pathology in tau transgenic in vivo models
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