Tyrosine kinase inhibition reverses TDP‐43 effects on synaptic protein expression, astrocytic function and amino acid dis‐homeostasis

Abstract

The trans-activating response of DNA/RNA-binding protein (TDP)-43 pathology is associated with many neurodegenerative diseases via unknown mechanisms. Here, we use a transgenic mouse model over-expressing human wild-type neuronal TDP-43 to study the effects of TDP-43 pathology on glutamate metabolism and synaptic function. We found that neuronal TDP-43 over-expression affects synaptic protein expression, including Synapsin I, and alters surrounding astrocytic function. TDP-43 over-expression is associated with an increase in glutamate and γ-amino butyric acid and reduction of glutamine and aspartate levels, indicating impairment of presynaptic terminal. TDP-43 also decreases tricarboxylic acid cycle metabolism and induces oxidative stress via lactate accumulation. Neuronal TDP-43 does not alter microglia activity or significantly changes systemic and brain inflammatory markers compared to control. We previously demonstrated that brain-penetrant tyrosine kinase inhibitors (TKIs), nilotinib and bosutinib, reduce TDP-43-induced cell death in transgenic mice. Here, we show that TKIs reverse the effects of TDP-43 on synaptic proteins, increase astrocytic function and restore glutamate and neurotransmitter balance in TDP-43 mice. Nilotinib, but not bosutinib, reverses mitochondrial impairment and oxidative metabolism. Taken together, these data suggest that TKIs can attenuate TDP-43 toxicity and improve synaptic and astrocytic function, independent of microglial or other inflammatory effects. In conclusion, our data demonstrate novel mechanisms of the effects of neuronal TDP-43 over-expression on synaptic protein expression and alteration of astrocytic function.

Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy

“…To probe numerous analytes, we utilize the Luminex xMAP technology [11, 15, 17, 24]. Kidney injury analytes were measured in serum with the Mouse Kidney Injury Magnetic Bead Panel 1 (Cat MKI1MAG-94K, EMD Millipore).…”

“…Our group has previously shown that FDA-approved tyrosine kinase inhibitors (TKIs) nilotinib (Tasigna®) and bosutinib (Bosulif®) are potential therapeutics for neurodegenerative diseases [11-17]. These findings led to phase II clinical trials currently underway.…”

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

“…Accordingly, lactate supplementation rescues motor neurons in co-culture with hSOD1 G93A astrocytes [74]. On the other hand, an increase in lactate levels has been described in the brain of a TDP-43 mouse model [105]. Regardless, a better understanding of the changes in astrocyte-neuron metabolic coupling in the disease may lead to therapeutic interventions aimed at enhancing astrocytic neuronal metabolic support.…”

TDP-43 in the spectrum of MND-FTLD pathologies

“…TDP-43 may also be involved in local translation in the synapse, translocating into dendrites in an activity-dependent manner (Wang, Wu, Chang, & Shen, 2008). Recently, we showed that TDP-43 controls mRNA expression of synaptic proteins such as synapsin I, leading to alterations in protein levels of synaptic proteins (Heyburn, et al, 2016). Together, the role of TDP-43 in regulation of gene expression is wide-reaching and disruption of TDP-43 in disease can affect all of these cellular processes, leading to cellular pathology.…”

“…Another study using a Drosophila model shows that the Drosophila homolog of TDP-43, TBPH binds to and regulates the expression of the mRNA of syntaxin 1A, which is a vesicular protein involved in vesicular fusion and exocytosis (Romano, et al, 2014). Our group has found that TDP-43 controls the expression of the synaptic proteins synapsin I and synaptotagmin (Heyburn, et al, 2016). Overexpression of TDP-43 in neurons leads to decreased expression of these proteins, providing further evidence of the importance of TDP-43 for synaptic function (Heyburn, et al, 2016).…”