Cellular mechanisms of protein aggregate propagation

Brandon B. Holmes, Marc I. Diamond

Research output: Contribution to journalReview articlepeer-review

51 Scopus citations


PURPOSE OF REVIEW: New research on the mechanisms of neurodegeneration highlights parallels between prion disease pathogenesis and other, more common disorders not typically thought to be infectious. This involves propagation of protein misfolding from cell to cell by templated conformational change. This review focuses on the cell biology that underlies propagation of protein aggregation between cells, including a discussion of protein biochemistry and relevant mouse models. RECENT FINDINGS: Like the prion protein, several other proteins exhibit self-propagating fibrillar conformations in vitro. Multiple cellular studies have now implicated endocytic mechanisms in the uptake of aggregates into cells. Aggregates that enter cells somehow escape endocytic vesicles to contact cytosolic protein. The mechanism of release of protein monomers and aggregates from cells is not well understood. Animal models have confirmed that brain lysates and purified protein can accelerate brain pathology in a manner similar to prions. SUMMARY: Aggregate flux in and out of cells likely contributes to the progression of neuropathology in neurodegenerative diseases. A better understanding of these mechanisms is emerging and can help explain local spread of protein aggregation and the role of neural networks in disease. This will also inform new therapeutic strategies aimed at blocking this process.

Original languageEnglish (US)
Pages (from-to)721-726
Number of pages6
JournalCurrent opinion in neurology
Issue number6
StatePublished - Dec 2012


  • cell-cell propagation
  • networks
  • neurodegeneration
  • prion
  • templated conformational change

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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