There are two primary mechanisms by which cells turn over cellular content. The ubiquitin-proteasome system degrades normal monomeric proteins and polypeptides. It involves tagging of the substrate protein by covalent attachment of multiple ubiquitin molecules and subsequent degradation of the tagged protein by the 26S proteasome. The second pathway, autophagy, directs proteins and organelles to lysosomes. There are three different types of autophagy: chaperone-mediated autophagy (CMA), macroautophagy, microautophagy. CMA mediates only degradation of soluble proteins. Single protein molecules are recognized by a specific cytosolic chaperone and a receptor on the lysosomal membrane, which then facilitate translocation of the protein into the lysosomal lumen. On induction of macroautophagy, cytoplasmic content or an organelle is sequestered inside double-membrane vesicles called autophagosomes. The autophagosomes subsequently fuse to the lysosomes for degradation and recycling. In microautophagy, cytosolic content can be sequestered directly by direct invagination of the lysosomal membrane.
|Upper panel: neurons expressing a morphology marker mApple2 (red) and the first exon of mutant huntingtin fused to EGFP (green). The yellow fluorescence labels inclusion bodies formed by mutant huntingtin, and reflects the overlap between red mApple2 and green EGFP. Middle panel: Electron micrograph of striatal neurons undergoing autophagy. Note the two mitochondria engulfed by an autophagosome. Lower panel: cultured striatal neurons stained with antibodies against MAP2 (red), DARPP-32 (green), and a nuclear Hoechst stain (blue).|
Abnormal intracellular protein deposits and damaged organelles characterize many neurodegenerative disorders. Neurons are less able to degrade abnormal proteins and damaged organelles as they become older, linking the build up of protein deposits and organelles and the appearance of adult-onset neurodegenerative disorders. My research focuses on the physiological and pathophysiological functions of macroautophagy in age-associated neuronal dysfunction and neurodegeneration. Our studies strongly suggest that at least some autophagic pathways can be modified with autophagy enhancers to boost degradation of abnormal protein, resulting in improved neuronal health. The ability of autophagy enhancers to increase removal of toxic material suggests that age-associated neurodegeneration can be halted or even reversed.
In the lab we use multiple approaches, including molecular, cell, and chemical biology, and microscopy techniques to understand molecular mechanisms of neuronal autophagy.
Moruno Manchon JF, Uzor N-E, Dabaghian Y, Furr-Stimming EE, Finkbeiner S, Tsvetkov AS. (2015) Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy. Sci Rep. 5, 15213; doi: 10.1038/srep15213
Tsvetkov AS, Arrasate M, Barmada S, Ando DM, Sharma P, Shaby BA, Finkbeiner S. (2013) Proteostasis of polygultamine varies among neurons and predicts neurodegeneration. Nat Chem Biol. 9(9):586-92.
Tsvetkov AS, Ando DM, Finkbeiner S. (2013) Longitudinal imaging of neurons expressing polyQ-expanded proteins. Methods Mol Biol. 1017:1-20.
Aron R, Tsvetkov A, Finkbeiner S. (2013) NUB1 snubs huntingtin toxicity. Nat Neurosci. 16(5):523-5.
Tsvetkov AS, Miller J, Arrasate M, Wong JS, Pleiss MA, Finkbeiner S. (2010) A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc Natl Acad Sci USA. 107(39):16982-7.
Mitra S, Tsvetkov AS, Finkbeiner S. (2009) Protein turnover and inclusion body formation. Autophagy. 5: 1037–1038.
Montie H, Cho M, Holder L, Tsvetkov AS, Finkbeiner S, Merry DE. (2009) Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet. 18(11):1937-50.
Mitra S, Tsvetkov AS, Finkbeiner S. (2009) Single-neuron ubiquitin-proteasome dynamics accompanying inclusion body formation in Huntington’s disease. J Biol Chem. 284(7):4398-403.
Search PubMed for additional articles.