title: 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.
authors: Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA.|Department of Pathology, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors: Lanier
authors: L
authors: Heyburn
authors: Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors: Michaeline L
authors: ML
authors: Hebron
authors: Drug Discovery Center, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors: Jacqueline
authors: J
authors: Smith
authors: Trauma and Dementia Laboratory, Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors: Charisse
authors: C
authors: Winston
authors: Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors: John
authors: J
authors: Bechara
authors: Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA.|School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, China.
authors: Zhaoxia
authors: Z
authors: Li
authors: Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors: Irina
authors: I
authors: Lonskaya
authors: Trauma and Dementia Laboratory, Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors: Mark P
authors: MP
authors: Burns
authors: Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA.|Department of Pathology, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors: Brent T
authors: BT
authors: Harris
authors: Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors: Charbel E-H
authors: CE
authors: Moussa
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D015870:Gene Expression; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D016704:Synapsins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016704:Synapsins; C578077:Tardbp protein, mouse
keywords: TDP-43; astrocytes; tyrosine kinase inhibition