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The Journal of Neuroscience, May 9, 2007, 27(19):5081-5091; doi:10.1523/JNEUROSCI.0957-07.2007

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Neurobiology of Disease
Defective Retrotranslocation Causes Loss of Anti-Bax Function in Human Familial Prion Protein Mutants

Julie Jodoin,^1,2 Stéphanie Laroche-Pierre,^1,2 Cynthia G. Goodyer,³ and Andréa C. LeBlanc^1,2

¹Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec, Canada H3T 1E2, and ²Departments of Neurology and Neurosurgery and ³Pediatrics, McGill University, Montréal, Québec, Canada H3A 2T5

Correspondence should be addressed to Dr. Andréa LeBlanc, The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis Jewish General Hospital, 3755 chemin Côte Ste-Catherine, Montréal, Québec, Canada H3T 1E2. Email: andrea.leblanc{at}mcgill.ca

Prion protein (PrP) inhibits the activation of proapoptotic Bax in primary human neurons and MCF-7 cells. Because neuronal apoptosis occurs in human prion diseases, here we examine the anti-Bax function of familial PrP mutants. All Creutzfeldt-Jakob disease and fatal familial insomnia-associated prion protein mutations partially or completely lose the anti-Bax function in human neurons and, except for A117V and V203I, in MCF-7 cells. The ability of the mutants to protect against Bax-mediated cell death is divided into three groups: (1) group I, retention of anti-Bax function in both the Val¹²⁹ and Met¹²⁹ mutants; (2) group II, retention of anti-Bax function only in Val¹²⁹ mutants; and (3) group III, reduction or no anti-Bax function in Val¹²⁹ and Met¹²⁹ mutants. The loss of anti-Bax function in these PrP mutants correlates completely with a significant decrease in the production of cytosolic PrP, a form of PrP shown previously to have anti-Bax function in human neurons. Cotransfection of the full-length PrP mutants with wild-type or mutant cytosolic PrP, but not with wild type full-length PrP, rescues the anti-Bax function of PrP. The results show that the failure of PrP mutants to produce cytosolic PrP is responsible for the loss of anti-Bax function and that the effect of the PrP mutants is dominant over wild-type PrP. Furthermore, these results imply that misfolded PrP that escapes retrotranslocation could accumulate at the cell surface and cause neuronal dysfunction.

Key words: prion protein; apoptosis; Bax; familial prion protein mutations; cytosolic PrP; retrotranslocation

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Received Jan. 30, 2006; accepted March 22, 2007.

Correspondence should be addressed to Dr. Andréa LeBlanc, The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis Jewish General Hospital, 3755 chemin Côte Ste-Catherine, Montréal, Québec, Canada H3T 1E2. Email: andrea.leblanc{at}mcgill.ca

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