Presenilin 1 forms aggresomal deposits in response to heat shock.
Aggresomes have been described as cytoplasmic membrane protein aggregates that are induced by proteasome inhibition or overexpression of certain proteins. Here, we characterized aggresomes formed by the Alzheimer's disease-associated presenilin 1 (PS1) protein. Proteasome inhibition induced accumulation of PS1 in the endoplasmic reticulum (ER) and retrotranslocation of the protein from the ER membrane into the cytoplasm. Aggresomes formed by PS1 modified the ER structure whereas proteasomes were inhibited. Therefore, clear visual identification of PS1 aggresomes required removal of the proteasome inhibitor followed by hours of recovery to redistribute the ER throughout the cells. Aggresomes formed by PS1 did not potentiate or attenuate apoptotic cell death induced by staurosporine treatment. Selective presence of the heat-shock proteins Hsp70 and HDJ-2/HSDJ, but not Hsp90, in aggresomes suggested chaperone-mediated transport of PS1 into these structures. Because proteasome inhibition and heat shock are both known to induce expression of heat shock proteins, we also demonstrated that heat shock alone was sufficient to induce PS1 aggresome formation and Hsp70 expression. These results indicate that aggresome formation by PS1 is chaperone-mediated and can be induced in response to heat-shock stress, a common cellular event in neurodegenerative diseases. Malfunctioning of the proteasome or heat-shock stress response in the brains of patients affected by Alzheimer's disease may lead to the accumulation of stable aggresomes of PS1, perhaps contributing to neurodegeneration.
Kovacs
Imre
I
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit/MIND, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Lentini
Kristen M
KM
Ingano
Laura MacKenzie
LM
Kovacs
Dora M
DM
D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D007976:Leupeptins / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D007976:Leupeptins; D053764:Presenilin-1; D061988:Proteasome Inhibitors; D011993:Recombinant Fusion Proteins; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde