Reversible Behavioral Phenotypes in a Conditional Mouse Model of TDP-43 Proteinopathies

Alfieri, Julio Armando; Pino, Natalia S.; Igaz, Lionel M.

doi:10.1523/jneurosci.1918-14.2014

Cited by 52 publications

(85 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, direct comparison of functional deficits between mouse models and human disease should be made carefully, and may rather reflect surrogate readout of functionally compromised neurons [24]. Earlier mutant human TDP-43 transgenic mice and rats present with memory deficits [1,38,39], similar to those seen in our iTDP-43 A315T mice with severe hippocampal atrophy. Memory deficits in bvFTD can be as severe as in AD [12,18], and may present with hippocampal atrophy as in AD [19].…”

Section: Discussionsupporting

confidence: 62%

“…Similarly, short-term suppression of transgenic expression of a TDP-43 variant that was artificially located to the cytoplasm by deleting the nuclear localization sequence (∆NLS) resulted in reversal of distinct functional deficits in young mice [1]. Once neurodegeneration was overt, suppression of transgenic TDP-43∆NLS expression did not improve functional deficits [1]. Similarly, memory deficits in our iTDP-43 A315T mice did not recover when transgenic TDP-43 was removed.…”

Section: Discussionmentioning

confidence: 82%

“…Conversely, the marked reversal of disinhibition/reduced anxiety in the elevated plus maze and hyperactivity in the open field suggests that these deficits result rather from function impairment of neurons by iTDP-43 A315T rather than neurodegeneration. Similarly, short-term suppression of transgenic expression of a TDP-43 variant that was artificially located to the cytoplasm by deleting the nuclear localization sequence (∆NLS) resulted in reversal of distinct functional deficits in young mice [1]. Once neurodegeneration was overt, suppression of transgenic TDP-43∆NLS expression did not improve functional deficits [1].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the inducible transgene expression system allows for different temporal scenarios of TDP-43 A315T expression; for example, future studies should investigate iTDP-43 A315T mice in which transgene expression was suppressed until after weaning to allow brain maturation before the transgene is expressed [24]. Similar studies in other inducible TDP-43 transgenic lines have shown differences in neuropathology when the transgene was activated in the adult brain, warranting further studies [1,5].…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Hummel

Stevens³

et al. 2015

Acta Neuropathol

View full text Add to dashboard Cite

The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Hummel

Stevens³

et al. 2015

Acta Neuropathol

View full text Add to dashboard Cite

show abstract

“…We used an established three-chamber box test [64,65]. Briefly, the testing apparatus consisted of a clear Plexiglas rectangular box (60 × 40 × 22 cm) with three interconnected chambers, placed under dim light (25 lux).…”

Section: Social Interaction and Social Novelty Assaysmentioning

confidence: 99%

Lrig1 is a cell‐intrinsic modulator of hippocampal dendrite complexity and BDNF signaling

et al. 2016

View full text Add to dashboard Cite

Even though many extracellular factors have been identified as promoters of general dendritic growth and branching, little is known about the cell-intrinsic modulators that allow neurons to sculpt distinctive patterns of dendrite arborization. Here, we identify Lrig1, a nervous system-enriched LRR protein, as a key physiological regulator of dendrite complexity of hippocampal pyramidal neurons. Lrig1-deficient mice display morphological changes in proximal dendrite arborization and defects in social interaction. Specifically, knockdown of Lrig1 enhances both primary dendrite formation and proximal dendritic branching of hippocampal neurons, two phenotypes that resemble the effect of BDNF on these neurons. In addition, we show that Lrig1 physically interacts with TrkB and attenuates BDNF signaling. Gain and loss of function assays indicate that Lrig1 restricts BDNF-induced dendrite morphology. Together, our findings reveal a novel and essential role of Lrig1 in regulating morphogenic events that shape the hippocampal circuits and establish that the assembly of TrkB with Lrig1 represents a key mechanism for understanding how specific neuronal populations expand the repertoire of responses to BDNF during brain development.

show abstract

Rodent Models of Amyotrophic Lateral Sclerosis

2015

View full text Add to dashboard Cite

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the CNS. Patients with ALS develop extensive muscle wasting and atrophy leading to paralysis and death 3-5 years after disease onset. ALS may be familial (fALS 10%) or sporadic ALS (sALS, 90%). The large majority of fALS) cases are due to genetic mutations in the Superoxide dismutase 1 gene (SOD1, 15% of fALS) and repeat nucleotide expansions in the gene encoding C9ORF72 (around 40-50% of fALS and ~10% of sALS). From a wide range of pathological studies the general conclusion is that ALS disease is mediated through aberrant protein homeostasis (ie ER stress and autophagy) and/or changes in RNA processing (as seen in all non-SOD1-mediated ALS). In all of these cases, animal models suggest that the disease is mediated non-cell-autonomously, i.e. not only motor neurons are involved, but glial cells including microglia, astrocytes and oligodendrocytes and other neuronal subpopulations are also implicated in disease pathogenesis. This overview will give a chronological overview of a wide range of different ALS rodent models generated so far with a thorough description of their intrinsic advantages and disadvantages. We will focus on their respective correlation with disease as seen in humans and their potential for understanding basic disease biology. As RNA processing has more recently come to the foreground of ALS research, we will mainly focus on a thorough description of the most recently generated ALS rodent models.

show abstract

Reversible Behavioral Phenotypes in a Conditional Mouse Model of TDP-43 Proteinopathies

Cited by 52 publications

References 52 publications

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Lrig1 is a cell‐intrinsic modulator of hippocampal dendrite complexity and BDNF signaling

Rodent Models of Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About