Abstract
ABSTRACTMacroautophagy/autophagy dysfunction is associated with many neurodegenerative diseases. TFEB (transcription factor EB), an important molecule that regulates lysosomal and autophagy function, is regarded as a potential target for treating some neurodegenerative diseases. However, the relationship between autophagy dysfunction and spiral ganglion neuron (SGN) degeneration and the role of TFEB in SGN degeneration has not yet been established. Here, we showed that in degenerated SGNs, induced by sensory epithelial cell loss in the cochlea of mice following kanamycin and furosemide administration, the lipofuscin area and oxidative stress level were increased, the nuclear-to-cytoplasmic TFEB ratio was decreased, and the late stage of autophagic flux was impaired. After autophagy dysfunction was partially ameliorated with an MTOR inhibitor, which promoted TFEB translocation into the nucleus from the cytoplasm, we found that the lysosomal deficits were significantly relieved, the oxidative stress level was reduced, and the density of surviving SGNs and auditory nerve fibers was increased. The results in the present study reveal that autophagy dysfunction is an important component of SGN degeneration, and TFEB may be a potential target for attenuating SGN degeneration following sensory epithelial cell loss in the cochlea of mice.Abbreviations: 3-NT: 3-nitrotyrosine; 4-HNE: 4-hydroxynonenal; 8-OHdG: 8-hydroxy-2ʹ-deoxyguanosine; ABR: auditory brainstem response; APP: amyloid beta (A4) precursor protein; CLEAR: coordinated lysosomal expression and regulation; CTSB: cathespin B; CTSD: cathespin D; SAMR1: senescence-accelerated mouse/resistance 1; SAMP8: senescence-accelerated mouse/prone 8; MAPK1/ERK2: mitogen-activated protein kinase 1; MTOR: mechanistic target of rapamycin kinase; SGN: spiral ganglion neuron; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscope; TFEB: transcription factor EB
Highlights
Sensorineural hearing loss is a common sensory disease that seriously affects physical and mental health and quality of life in humans
The structure of the organ of Corti was completely collapsed and disintegrated, nearly no sensory epithelial cells remained on the 30th day after kanamycin and furosemide administration, and the basilar membrane was covered by a continuous layer of flattened cubic epithelial cells
Because spiral ganglion neuron (SGN) degeneration was aggravated following sensory epithelial cell loss in the cochleae of mice, lipofuscin gradually accumulated in the SGNs (Figure 3 (a,b)), and the area of the cytoplasm occupied by lipofuscin granules increased (Figure 3(f))
Summary
Sensorineural hearing loss is a common sensory disease that seriously affects physical and mental health and quality of life in humans. The pathogenic factors are diverse, the underlying pathological features of sensorineural hearing loss are similar: sensory epithelial cell (hair cell and support cell) loss and the progressive degeneration of cochlear nerve fibers and spiral ganglion neurons (SGNs). Many pathogenic factors resulting in sensorineural hearing loss mainly cause sensory epithelial cells to be destroyed in the cochlea and do not cause simultaneous SGN injuries. As a consequence of cochlear sensory epithelial cell loss, the degeneration of cochlear nerve fibers and SGNs is, in essence, atrophy from disuse, which results from the loss of the target organ and neurotrophic factors [1]. To rehabilitate hearing diminished by sensorineural hearing loss, preventing or alleviating the degeneration of cochlear nerve fibers and SGNs following sensory epithelial cell loss is crucial
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