期刊
AUTOPHAGY
卷 14, 期 8, 页码 1419-1434出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2018.1474313
关键词
Autophagic vacuoles; autophagy; ERG; lysosomal storage diseases; MPS IIIB; mucopolysaccharidosis type IIIB; retina; Sanfilippo syndrome; TFEB; trehalose
类别
资金
- NIH [NS079618, 1S10 OD016167]
- Sanfilippo Foundation
- Swiss Sanfilippo Foundation
- Brain Disorders and Development Training grant [T32NS043124-13]
- Hamill Foundation
- IDDRC grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development [1U54 HD083092]
- Hong Kong Polytechnic University grant G-YBQT
- Hong Kong Polytechnic University grant [1-ZE6H]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD083092] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [P30EY002520, R01EY019908] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007526] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R56NS079618, R01NS079618, T32NS043124] Funding Source: NIH RePORTER
The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose. Treated naglu(-/ -) mice lived longer, displayed less hyperactivity and anxiety, retained their vision (and retinal photoreceptors), and showed reduced inflammation in the brain and retina. Treated mice also showed improved clearance of autophagic vacuoles in neuronal and glial cells, accompanied by activation of the TFEB transcriptional network that controls lysosomal biogenesis and autophagic flux. Therefore, small-molecule-induced autophagy enhancement can improve the neurological symptoms associated with a lysosomal enzyme deficiency and could provide a viable therapeutic approach to neuropathic LSDs.Abbreviations: ANOVA: analysis of variance; Atg7: autophagy related 7; AV: autophagic vacuoles; CD68: cd68 antigen; ERG: electroretinogram; ERT: enzyme replacement therapy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GNAT2: guanine nucleotide binding protein, alpha transducing 2; HSCT: hematopoietic stem cell transplantation; INL: inner nuclear layer; LC3: microtubule-associated protein 1 light chain 3 alpha; MPS: mucopolysaccharidoses; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); ONL: outer nuclear layer; PBS: phosphate-buffered saline; PRKCA/PKC: protein kinase C, alpha; S1BF: somatosensory cortex; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VMP/VPL: ventral posterior nuclei of the thalamus
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