Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy

Aberrant α-synuclein degradation is implicated in Parkinson's disease pathogenesis because the protein accumulates in the Lewy inclusion bodies associated with the disease. Little is known, however, about the pathways by which wild-type α-synuclein is normally degraded. We found that wild-type α-synuclein was selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway. The pathogenic A53T and A30P α-synuclein mutants bound to the receptor for this pathway on the lysosomal membrane, but appeared to act as uptake blockers, inhibiting both their own degradation and that of other substrates. These findings may underlie the toxic gain-of-function by the mutants.

[1]  J. Dice.  Lysosomal Pathways of Protein Degradation , 2000 .

[2]  A. Ciechanover,et al.  The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. , 2002, Physiological reviews.

[3]  Barry Halliwell,et al.  Failure of the ubiquitin–proteasome system in Parkinson's disease , 2001, Nature Reviews Neuroscience.

[4]  E. Knecht,et al.  Import of a cytosolic protein into lysosomes by chaperone-mediated autophagy depends on its folding state. , 2000, The Journal of biological chemistry.

[5]  M. Spillantini,et al.  α‐Synuclein metabolism and aggregation is linked to ubiquitin‐independent degradation by the proteasome , 2001, FEBS letters.

[6]  D Baker,et al.  Mechanisms of protein folding. , 2001, Current opinion in structural biology.

[7]  F. Checler,et al.  α-Synuclein and the Parkinson's disease-related mutant Ala53Thr-α-synuclein do not undergo proteasomal degradation in HEK293 and neuronal cells , 2000, Neuroscience Letters.

[8]  M. Polymeropoulos,et al.  Genetics of Parkinson's disease. , 1997, Human molecular genetics.

[9]  Jeremy N. Skepper,et al.  α-Synuclein Is Degraded by Both Autophagy and the Proteasome* , 2003, Journal of Biological Chemistry.

[10]  T. Chase,et al.  Degradation of α-Synuclein by Proteasome* , 1999, The Journal of Biological Chemistry.

[11]  A. Rivett,et al.  Changes in the proteolytic activities of proteasomes and lysosomes in human fibroblasts produced by serum withdrawal, amino-acid deprivation and confluent conditions. , 2003, The Biochemical journal.

[12]  A. Cuervo,et al.  A Receptor for the Selective Uptake and Degradation of Proteins by Lysosomes , 1996, Science.

[13]  Christina A. Wilson,et al.  Degradative organelles containing mislocalized α- and β-synuclein proliferate in presenilin-1 null neurons , 2004, The Journal of cell biology.

[14]  He-Jin Lee,et al.  Clearance of α-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway , 2004, The Journal of Neuroscience.

[15]  A. Cuervo,et al.  A Population of Rat Liver Lysosomes Responsible for the Selective Uptake and Degradation of Cytosolic Proteins* , 1997, The Journal of Biological Chemistry.

[16]  D. Sulzer,et al.  Proteasomal inhibition leads to formation of ubiquitin/α‐synuclein‐immunoreactive inclusions in PC12 cells , 2001, Journal of neurochemistry.

[17]  A. Cuervo,et al.  Lysosomes, a meeting point of proteins, chaperones, and proteases , 1997, Journal of Molecular Medicine.

[18]  A. Cuervo.  Autophagy: in sickness and in health. , 2004, Trends in cell biology.

[19]  P. Lansbury,et al.  Vesicle permeabilization by protofibrillar alpha-synuclein: implications for the pathogenesis and treatment of Parkinson's disease. , 2001, Biochemistry.

[20]  D. Sulzer,et al.  Autophagy in neurons: a review. , 2002, Histology and histopathology.

[21]  Heidi Phillips,et al.  Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System , 2000, Neuron.

[22]  A. Cuervo,et al.  Selective binding and uptake of ribonuclease A and glyceraldehyde-3-phosphate dehydrogenase by isolated rat liver lysosomes. , 1994, The Journal of biological chemistry.

[23]  Dice Jf.  Peptide sequences that target cytosolic proteins for lysosomal proteolysis , 1990 .

[24]  L. Stefanis,et al.  Proteasomal Inhibition-Induced Inclusion Formation and Death in Cortical Neurons Require Transcription and Ubiquitination , 2002, Molecular and Cellular Neuroscience.

[25]  John Q. Trojanowski,et al.  Induction of α-Synuclein Aggregation by Intracellular Nitrative Insult , 2001, The Journal of Neuroscience.

[26]  W. Dauer,et al.  Parkinson's Disease Mechanisms and Models , 2003, Neuron.

[27]  L. Greene,et al.  Expression of A53T Mutant But Not Wild-Type α-Synuclein in PC12 Cells Induces Alterations of the Ubiquitin-Dependent Degradation System, Loss of Dopamine Release, and Autophagic Cell Death , 2001, The Journal of Neuroscience.