Entorhinal Cortical Neurons Are the Primary Targets of FUS Mislocalization and Ubiquitin Aggregation in FUS Transgenic Rats

The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
Human Molecular Genetics (Impact Factor: 6.39). 07/2012; 21(21):4602-14. DOI: 10.1093/hmg/dds299
Source: PubMed


Ubiquitin-positive inclusion containing Fused in Sarcoma (FUS) defines a new subtype of frontotemporal lobar degeneration (FTLD). FTLD is characterized by progressive alteration in cognitions and it preferentially affects the superficial layers of frontotemporal cortex. Mutation of FUS is linked to amyotrophic lateral sclerosis and to motor neuron disease with FTLD. To examine FUS pathology in FTLD, we developed the first mammalian animal model expressing human FUS with pathogenic mutation and developing progressive loss of memory. In FUS transgenic rats, ubiquitin aggregation and FUS mislocalization were developed primarily in the entorhinal cortex of temporal lobe, particularly in the superficial layers of affected cortex. Overexpression of mutant FUS led to Golgi fragmentation and mitochondrion aggregation. Intriguingly, aggregated ubiquitin was not colocalized with either fragmented Golgi or aggregated mitochondria, and neurons with ubiquitin aggregates were deprived of endogenous TDP-43. Agonists of peroxisome proliferator-activated receptor gamma (PPAR-γ) possess anti-glial inflammation effects and are also shown to preserve the dendrite and dendritic spines of cortical neurons in culture. Here we show that rosiglitazone, a PPAR-γ agonist, rescued the dendrites and dendritic spines of neurons from FUS toxicity and preserved rats' spatial memory. Our FUS transgenic rats would be useful to the mechanistic study of cortical dementia in FTLD. As rosiglitazone is clinically used to treat diabetes, our results would encourage immediate application of PPAR-γ agonists in treating patients with cortical dementia.

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    • "Golgi fragmentation also occurs in transgenic ALS rodent models [25-27]. It has been identified as an early feature in motor neurons in transgenic mice that express human SOD1 with an ALS-linked mutation and develop an ALS like motor neuron disorder [27-29]. "
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    ABSTRACT: Fragmentation of stacked cisterns of the Golgi apparatus into dispersed smaller elements is a feature associated with degeneration of neurons in amyotrophic lateral sclerosis (ALS) and some other neurodegenerative disorders. However, the role of Golgi fragmentation in motor neuron degeneration is not well understood. Here we use a SOD1-ALS mouse model (low-copy Gurney G93A-SOD1 mouse) to show that motor neurons with Golgi fragmentation are retrogradely labeled by intramuscularly injected CTB (beta subunit of cholera toxin), indicating that Golgi fragmentation precedes neuromuscular denervation and axon retraction. We further show that Golgi fragmentation may occur in the absence of and precede two other pathological markers, i.e. somatodendritic SOD1 inclusions, and the induction of ATF3 expression. In addition, we show that Golgi fragmentation is associated with an altered dendritic organization of the Golgi apparatus, does not depend on intact apoptotic machinery, and is facilitated in transgenic mice with impaired retrograde dynein-dependent transport (BICD2-N mice). A connection to altered dynein-dependent transport also is suggested by reduced expression of endosomal markers in neurons with Golgi fragmentation, which also occurs in neurons with impaired dynein function. Together the data indicate that Golgi fragmentation is a very early event in the pathological cascade in ALS that is associated with altered organization of intracellular trafficking.
    04/2014; 2(1):38. DOI:10.1186/2051-5960-2-38
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    • "For double-labeling fluorescence staining, cells were fixed in 4% paraformaldehyde for 30 minutes and washed in 1X PBS twice. Fixed cells were incubated with primary and secondary antibodies sequentially and immunoreactivity was visualized with a Nikon fluorescence microscope as described previously 28. "
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    International journal of biological sciences 01/2013; 9(2):149-55. DOI:10.7150/ijbs.5617 · 4.51 Impact Factor
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    • "For the entire study, a total of 18 brains were analyzed; spines were counted from 42 neurons and along 360 basilar terminal tips (20 terminal dendritic tips per animal). The rationale for our protocol was based on a survey of the recent literature using Golgi staining and dendritic spine analysis in the hippocampus (Morgenstern et al. 2008; Adlard et al. 2011; Chapleau et al. 2012; Huang et al. 2012). "
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    ABSTRACT: Neurogenesis occurs throughout life but significantly decreases with age. Human umbilical cord blood mononuclear cells (HUCB MNCs) have been shown to increase the proliferation of neural stem cells (NSCs) in the dentate gyrus (DG) of the hippocampus and the subgranular zone of aging rats (Bachstetter et al., BMC Neurosci 9:22, 2008), but it is unclear which fraction or combination of the HUCB MNCs are responsible for neurogenesis. To address this issue, we examined the ability of HUCB MNCs, CD4+, CD8+, CD3+, CD14+, and CD133+ subpopulations to increase proliferation of NSCs both in vitro and in vivo. NSCs were first grown in conditioned media generated from HUCB cultures, and survival and proliferation of NSC were determined with the fluorescein diacetate/propidium iodide and 5-bromo-2'-deoxyuridine incorporation assays, respectively. In a second study, we injected HUCB cells intravenously in young and aged Fisher 344 rats and examined proliferation in the DG at 1 week (study 2.1) and 2 weeks (study 2.2) postinjection. The effects of the HUCB MNC fractions on dendritic spine density and microglial activation were also assessed. HUCB T cells (CD3+, CD4+, and CD8+ cells) induced proliferation of NSCs (pā€‰<ā€‰0.001) and increased cell survival. In vivo, HUCB-derived CD4+ cells increased NSC proliferation at both 1 and 2 weeks while also enhancing the density of dendritic spines at 1 week and decreasing inflammation at 2 weeks postinjection. Collectively, these data indicate that a single injection of HUCB-derived T cells induces long-lasting effects and may therefore have tremendous potential to improve aging neurogenesis.
    Age 12/2012; 35(6). DOI:10.1007/s11357-012-9496-5 · 3.45 Impact Factor
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