Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons

Neurodegenerative diseases display synaptic deficits, mitochondrial
defects, and protein aggregation. We show that intracellular ATP regulates
axoplasmic viscosity and protein aggregation in mammalian neurons.
Decreased intracellular ATP upon mitochondria inhibition leads to
axo-terminal cytosol, synaptic vesicles, and active zone components
condensation, modulating the functional organization of mouse
glutamatergic synapses. Proteins involved in the pathogenesis of
Parkinson’s disease (PD), Alzheimer's disease (AD), and Amyotrophic
Lateral Sclerosis (ALS) condensed and underwent ATP-dependent LPS in
vitro. Human iPSC-derived neurons from PD and ALS patients displayed a
reduction in their axoplasmic fluidity and decreased intracellular ATP.
Finally, nicotinamide mono-nucleotide (NMN) treatment successfully rescued
intracellular ATP levels and axoplasmic viscosity in neurons from PD and
ALS patients, and reduced TDP-43 aggregation in human motor neurons
derived from an ALS patient. Thus, our data suggest that the hydrotropic
activity of ATP contributes to the regulation of neuronal homeostasis in
both physiological and pathological conditions.

神经退行性疾病常表现为突触功能缺陷、线粒体异常及蛋白质聚集。本研究证实，细胞内三磷酸腺苷（ATP）可调控哺乳动物神经元的轴浆粘度与蛋白质聚集过程。线粒体抑制引发的细胞内ATP水平降低，会导致轴突末端胞浆、突触囊泡及活性区组分发生凝聚，进而调控小鼠谷氨酸能突触的功能组织架构。参与帕金森病（PD）、阿尔茨海默病（AD）及肌萎缩侧索硬化（ALS）发病机制的相关蛋白可发生凝聚，并在体外呈现ATP依赖的液液相分离。来自PD与ALS患者的诱导多能干细胞（iPSC）源性神经元，其轴浆流动性降低且细胞内ATP水平下降。最终，烟酰胺单核苷酸（NMN）干预可有效恢复PD与ALS患者神经元的细胞内ATP水平及轴浆粘度，并可降低ALS患者源性运动神经元中TDP-43的聚集水平。综上，本研究数据表明，ATP的增溶活性可在生理与病理状态下参与调控神经元稳态。