. Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol. Science. 2002 Nov 29;298(5599):1785-8. PubMed.


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  1. The papers by Ma and Lindquist are important to AD research. Unlike most other neurodegenerative diseases, AD and prion diseases have in common that both are characterized by dementia and "extracellular" plaques. The present papers demonstrate that increasing the intracellular "cytosolic" pool of PrP (i.e., by inhibition of the proteasome) is especially critical for neurotoxicity. In Alzheimer's research, a growing number of articles are also suggesting that β-amyloid accumulates within neurons and that intracellular Aβ may be neurotoxic. For example, just this year Zhang et al. reported that Aβ1-42, but not Aβ42-1 or Aβ1-40, was highly neurotoxic when introduced intracellularly, and Busciglio et al. reported that in Down's syndrome Aβ-accumulating neurons showed signs of apoptosis, see related news item.

    Still, the view that Aβ may be neurotoxic intracellularly, as it is for PrP in prion diseases, remains very controversial. These new papers on PrP should move research on prion diseases further into studying the subcellular biology of prion accumulation and how this is influenced by the proteasome. Both fields need to learn from the evolving work by cell biologists and neuroscientists working on the ubiquitin-protaosome system, since it is becoming increasingly apparent that degradation of proteins via this system may be critical to all neurodegenerative diseases, and AD research should not be left behind.


    . Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons. J Cell Biol. 2002 Feb 4;156(3):519-29. PubMed.

    . Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron. 2002 Feb 28;33(5):677-88. PubMed.

    View all comments by Gunnar Gouras

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  1. Shape-Shifting Prion Protein in Cytosol: Highly Toxic Yet Almost Invisible