Cytoplasmic mislocalization and mitochondrial colocalization of TDP-43 are common features between normal aged and young mice

Abstract

Transactive response DNA binding protein 43 (TDP-43) pathologies have been well recognized in various neurodegenerative disorders including frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). However, there have been limited studies on whether there are any TDP-43 alterations in normal aging. We investigated TDP-43 distribution in different brain regions in normal aged ( n = 3 for 26- or 36-month-old) compared to young ( n = 3 for 6- or 12-month-old) mice. In both normal aged and young mice, TDP-43 and phosphorylated TDP-43 (pTDP-43) demonstrated a unique pattern of distribution in neurons in some specific brain regions including the pontine nuclei, thalamus, CA3 region of the hippocampus, and orbital cortex. This pattern was demonstrated on higher magnification of high-resolution double fluorescence images and confocal microscopy as mislocalization of TDP-43 and pTDP-43, characterized by neuronal nuclear depletion and cytoplasmic accumulation in these brain regions, as well as colocalization between TDP-43 or pTDP-43 and mitochondria, similar to what has been described previously in neurodegenerative disorders. All these findings were identical in both normal aged and young mice. In summary, TDP-43 and pTDP-43 mislocalization from nucleus to cytoplasm and their colocalization with mitochondria in the specific brain regions are present not only in aging, but also in young healthy states. Our findings provide a new insight for the role of TDP-43 proteinopathy in health and diseases, and that aging may not be a critical factor for the development of TDP-43 proteinopathy in subpopulations of neurons. Impact statement Despite increasing evidence implicating the important role of TDP-43 in the pathogenesis of a wide range of age-related neurodegenerative diseases, there is limited study of TDP-43 proteinopathy and its association with mitochondria during normal aging. Our findings of cytoplasmic accumulation of TDP-43 that is highly colocalized with mitochondria in neurons in selective brain regions in young animals in the absence of neuronal loss provide a novel insight into the development of TDP-43 proteinopathy and its contribution to neuronal loss.

Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

“…Whether TDP-43 does have physiological functions in mitochondria is still unknown. As TDP-43 bears mitochondrial localization motifs [ 12 ] and as it is localized to mitochondria in non-pathological contexts [ 37 , 52 ], it is tempting to speculate that TDP-43 binds to mtDNA-encoded mRNAs, thereby regulating mitochondrial protein expression [ 36 ] ( Figure 1 A). In such a scenario, mitochondrial TDP-43 modulates mitochondrial functions, such as OXPHOS, in a physiological context.…”

“…Termsarasab and colleagues observed that endogenous TDP-43 is highly phosphorylated in mitochondria of the pontine nuclei, thalamus, Cornu Ammonis 3 (CA3) region of the hippocampus, and orbital cortex of young and normal aged mice without any evidence of neurodegenerative or systemic disorders [ 52 ]. Through high-resolution double fluorescence images and confocal microscopy, they revealed that mitochondrial TDP-43 localization in these brain regions was paralleled to nuclear depletion and cytoplasmic accumulation of this protein.…”

“…The TDP-43 accumulation in mitochondria in a disease context suggests a pathological function of mitochondrial TDP-43. However, physiological roles for the mitochondrial localization of this protein have also been proposed [ 36 , 52 ]. Before discussing how TDP-43 is involved in mitochondrion-dependent cell death, we, therefore, critically compare the evidence for the physiological and pathophysiological roles of mitochondrial TDP-43.…”

Maintaining the balance of TDP-43, mitochondria, and autophagy: a promising therapeutic strategy for neurodegenerative diseases

“…Additional evidence has shown that in the mouse model of motor neuron disease, full-length TDP-43 has increased associations with mitochondria, while blocking the TDP-43/mitochondrial interaction improves motor dysfunction [ 71 ]. Moreover, recent studies have reported that cytoplasmic mislocalization and mitochondrial localization of TDP-43 are common features in normal elderly mice [ 72 ].…”

Mechanisms of aging, age-associated diseases, and lifespan determination

“…Termsarasab et al. 17 report the results of their analysis of the subcellular localization of transactive response DNA-binding protein 43 (TDP-43) in young and old mice. In normal healthy cells, TDP-43 is expressed in the nucleus; however, TDP-43 has been shown to localize in the cytosol and mitochondria in the degenerating neurons of age-associated diseases such as Alzheimer’s disease.…”