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Chaperone-mediated autophagy is impa...

Sackler School of Graduate Biomedical Sciences (Tufts University)., Cellular & Molecular Physiology.

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Chaperone-mediated autophagy is impaired in Mucolipidosis type IV.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Chaperone-mediated autophagy is impaired in Mucolipidosis type IV./
Author:	Mesires, Nicholas T.
Description:	140 p.
Notes:	Adviser: James F. Dice.
Contained By:	Dissertation Abstracts International68-12B.
Subject:	Biology, Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3291151
ISBN:	9780549358848

Chaperone-mediated autophagy is impaired in Mucolipidosis type IV.
Mesires, Nicholas T.

Chaperone-mediated autophagy is impaired in Mucolipidosis type IV. - 140 p.

Adviser: James F. Dice.

Thesis (Ph.D.)--Sackler School of Graduate Biomedical Sciences (Tufts University), 2008.

Chaperone-mediated autophagy (CMA) is a selective autophagic pathway that is activated in fibroblasts in response to serum withdrawal and in the liver during periods of prolonged starvation. Cytosolic proteins with a motif containing the amino acids KFERQ are recognized by a chaperone complex containing heat shock cognate protein of 70 kDa (Hsc70) and are targeted to the lysosomal membrane. Substrate proteins bind to the lysosomal membrane through interaction with lysosome-associated membrane protein type 2A (LAMP-2A). An intralysosomal isoform of Hsc70 (ly-Hsc70) then facilitates the translocation of substrate proteins across the lysosomal membrane. Although many mechanistic aspects of CMA have been elucidated, the physiologic and pathologic consequences of CMA proteolysis are not completely understood. It is unknown how CMA is affected in Mucolipidosis type IV (MLIV), a lysosomal storage disease characterized by progressive psychomotor retardation, ophthalmologic abnormalities, and accumulation of heterogeneous storage material in virtually every tissue of the body. Preliminary evidence demonstrates the interaction of ly-Hsc70 with transient receptor potential mucolipin-1 protein (TRPML1), a non-specific cation channel localizing to late endosomes and lysosomes that is either not expressed or dysfunctional in MLIV. Based on these findings, we hypothesized that this interaction may be required for proper CMA activity in MLIV fibroblasts. CMA is defective in MLIV cells as measured by pulse chase analysis as well as in vitro proteolysis assays using isolated lysosomes. Decreased CMA proteolysis is accompanied by decreased levels of lysosomal LAMP-2A and decreased binding of CMA substrates to MLIV lysosomes. However, total levels of LAMP-2A are increased in MLIV fibroblasts, suggesting that LAMP-2A may not be properly trafficked to the lysosomal compartment in MLIV. Levels of oxidatively modified proteins are also increased in MLIV fibroblasts, and may be a result of impaired CMA in these cells. We conclude that CMA is impaired in MLIV fibroblasts due to decreased LAMP-2A levels in the lysosomal membrane and results in an increase in oxidatively modified proteins. Defects in CMA may be responsible for some aspects of the MLIV phenotype as well as exacerbate the progression of the disease.

ISBN: 9780549358848Subjects--Topical Terms:

1017816
Biology, Physiology.

Chaperone-mediated autophagy is impaired in Mucolipidosis type IV.
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245 1 0 $a Chaperone-mediated autophagy is impaired in Mucolipidosis type IV.
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500 $a Source: Dissertation Abstracts International, Volume: 68-12, Section: B, page: 7855.
502 $a Thesis (Ph.D.)--Sackler School of Graduate Biomedical Sciences (Tufts University), 2008.
520 $a Chaperone-mediated autophagy (CMA) is a selective autophagic pathway that is activated in fibroblasts in response to serum withdrawal and in the liver during periods of prolonged starvation. Cytosolic proteins with a motif containing the amino acids KFERQ are recognized by a chaperone complex containing heat shock cognate protein of 70 kDa (Hsc70) and are targeted to the lysosomal membrane. Substrate proteins bind to the lysosomal membrane through interaction with lysosome-associated membrane protein type 2A (LAMP-2A). An intralysosomal isoform of Hsc70 (ly-Hsc70) then facilitates the translocation of substrate proteins across the lysosomal membrane. Although many mechanistic aspects of CMA have been elucidated, the physiologic and pathologic consequences of CMA proteolysis are not completely understood. It is unknown how CMA is affected in Mucolipidosis type IV (MLIV), a lysosomal storage disease characterized by progressive psychomotor retardation, ophthalmologic abnormalities, and accumulation of heterogeneous storage material in virtually every tissue of the body. Preliminary evidence demonstrates the interaction of ly-Hsc70 with transient receptor potential mucolipin-1 protein (TRPML1), a non-specific cation channel localizing to late endosomes and lysosomes that is either not expressed or dysfunctional in MLIV. Based on these findings, we hypothesized that this interaction may be required for proper CMA activity in MLIV fibroblasts. CMA is defective in MLIV cells as measured by pulse chase analysis as well as in vitro proteolysis assays using isolated lysosomes. Decreased CMA proteolysis is accompanied by decreased levels of lysosomal LAMP-2A and decreased binding of CMA substrates to MLIV lysosomes. However, total levels of LAMP-2A are increased in MLIV fibroblasts, suggesting that LAMP-2A may not be properly trafficked to the lysosomal compartment in MLIV. Levels of oxidatively modified proteins are also increased in MLIV fibroblasts, and may be a result of impaired CMA in these cells. We conclude that CMA is impaired in MLIV fibroblasts due to decreased LAMP-2A levels in the lysosomal membrane and results in an increase in oxidatively modified proteins. Defects in CMA may be responsible for some aspects of the MLIV phenotype as well as exacerbate the progression of the disease.
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