Abstract
TDP-43 is an RNA-binding protein important for many aspects of RNA metabolism. Abnormal accumulation of TDP-43 in the cytoplasm of affected neurons is a pathological hallmark of the neurodegenerative diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Several transgenic mouse models have been generated that recapitulate defects in TDP-43 accumulation, thus causing neurodegeneration and behavioural impairments. While aging is the key risk factor for neurodegenerative diseases, the specific effect of aging on phenotypes in TDP-43 transgenic mice has not been investigated. Here, we analyse age-dependent changes in TDP-43 transgenic mice that displayed impaired memory. We found the accumulation of abundant poly-ubiquitinated protein aggregates in the hippocampus of aged TDP-43 transgenic mice. Intriguingly, the aggregates contained some interneuron-specific proteins such as parvalbumin and calretinin, suggesting that GABAergic interneurons were degenerated in these mice. The abundance of aggregates significantly increased with age and with the overexpression of TDP-43. Gene array analyses in the hippocampus and other brain areas revealed dysregulation in genes linked to oxidative stress and neuronal function in TDP-43 transgenic mice. Our results indicate that the interneuron degeneration occurs upon aging, and TDP-43 accelerates age-dependent neuronal degeneration, which may be related to the impaired memory of TDP-43 transgenic mice.
Highlights
Transactive response DNA binding protein of 43 kDa (TDP-43) is an RNA binding protein linked to the pathophysiology of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
To recapitulate the pathology of sporadic ALS/FTD in mice, we generated transgenic (Tg) mice in which full-length wild-type human TDP-43 was expressed under the control of the mouse prion promoter
We found that mice expressing exogenous TDP-43 display memory deficits, and massive p62- and poly-ubiquitin-positive aggregates are observed in the hippocampus of both aged non-Tg mice and TDP-43 Tg mice
Summary
Transactive response DNA binding protein of 43 kDa (TDP-43) is an RNA binding protein linked to the pathophysiology of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (for review, see Renton et al 20141). ALS is characterized by progressive and selective neurodegeneration of motor neurons, while FTD is characterized by progressive neuronal loss predominantly in the frontal and/or temporal lobes For both ALS and FTD, a fraction of the patients develop the inherited form of the disease. Several reports indicate that elevated levels of wild-type TDP-43 are sufficient to cause neurological and pathological phenotypes mimicking FTD/ALS in mice[15,16,17]. Transgenic (Tg) mice expressing elevated levels of wild-type TDP-43 are appropriate disease models to capture the pathology of sporadic ALS/FTD in mice. To define the pathomechanisms of sporadic ALS/FTD and to investigate the contribution of aging to the formation of such phenotypes, we generated Tg mice expressing wild-type TDP-43 under the control of the mouse prion promoter and defined the pathology, behaviour, and genes affected by the dysregulation of TDP43 during aging. We observed the aggregates in aged wild-type mice; the aggregates increased as the animals got older, indicating that the degeneration of GABAergic interneurons occurs during aging and is accelerated by the increased accumulation of TDP-43
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