insight review articles900 NATURE|VOL 426|18/25 DECEMBER 2003|www.nature.com/natureOne of the most satisfying moments in scientificinvestigation occurs when previously disparatephenomena of unclear origin are shown to arisefrom a common principle. During the pastdecade, numerous aetiologically distinct dis-eases have been linked by the likelihood that they result fromthe progressive misfolding of specific proteins into aggre-gates that can injure and kill cells. Together, these disordersinflict enormous personal and societal burdens, making itcrucial to understand their genesis and to learn how to prevent them.The amyloidoses have traditionally been defined as diseases in which normally soluble proteins accumulate inthe extracellular space of various tissues as insolubledeposits of 10 nm fibrils that are rich in b-sheet structureand have characteristic dye-binding properties1,2. There aremany examples of secreted, circulating proteins that can,under abnormal circumstances, be converted in part tohighly stable extracellular fibrils. These includeimmunoglobulins in primary systemic amyloidosis andmultiple myeloma, amylin in the diabetic pancreas, andsmall soluble proteins of uncertain function such as theamyloid b-peptide (Ab) in Alzheimer’s disease.Although the specific polypeptides that comprise thedeposits are different for each amyloidosis, the disordershave several key features in common. Perhaps foremostamong them is the ability of proteins that are highly solublein biological fluids to be converted gradually to insoluble fil-amentous polymers enriched in b-pleated sheet conforma-tion. The common structural motif of virtually all amyloidfibrils consists of cross-b-sheets in which the peptidestrands are arranged perpendicular to the long axis of thefibre. Although it was once thought that relatively few pro-teins have this propensity, recent data suggest that many sol-uble proteins can, under certain circumstances, undergothis conversion. Of particular significance is the finding thatglobular proteins with diverse sequences that are not cur-rently associated with a protein-folding disease (for exam-ple, muscle myoglobin) can undergo aggregation in vitrointo fibrils indistinguishable from those found in theamyloidoses3,4. This finding supports the concept thataggregation into b-sheet-rich fibrils is a generic property ofpolypeptide chains regardless of sequence5.Another general feature of protein-folding disorders isthe prolonged period before clinical manifestations appear.Although the age of onset of symptoms varies widely amongthe different diseases and even among cases of one disease,most of these disorders become noticeable in middle or latelife. There is a prolonged preclinical phase during whichproteins misfold, build up and progressively compromisecellular and tissue function. A portion of this long pro-drome derives from the energetic barriers to the formationof misfolded species, including the fact that nucleation —the initial development of very small, metastable oligomersof a protein — is a kinetically unfavourable requirement forfibrillogenesis6,7. It seems that time, rather than great age, isrequired, in that some aggressive protein-folding disorderscan occur in young and early middle-aged individuals. Insuch cases, time still has a role but the fibrillogenic processrequires less time overall because particular biochemicalcircumstances promote accelerated nucleation. One strik-ing example is Down’s syndrome, in which patients with tri-somy 21 develop abundant Ab aggregates in the brain asearly as the age of ten, owing to lifelong overexpression of theb-amyloid precursor protein (APP), which is encoded onchromosome 21. Similarly, inherited missense mutations inamyloid-prone proteins can markedly accelerate their mis-folding and fibrillogenesis, producing earlier disease onsetthan occurs with the wild-type isoform. For example, senilesystemic amyloidosis arises late in life from the aggregationof wild-type transthyretin, whereas familial amyloidoticpolyneuropathy I generally arises in mid-life from the accel-erated aggregation of mutant transthyretin.In this review, I describe briefly three types of amyloidosis: systemic, organ-limited and intracellular. Ithen examine how abberant protein folding may occur andhow misfolded proteins may disrupt the cell. Systemic amyloidosesThe list of secreted, circulating proteins that are capable ofproducing extracellular amyloid deposits in multipleorgans is long and growing (Table 1). Amyloidoses can arisewhen other pathological conditions cause a sharp increasein the concentration of an amyloid-prone polypeptide, asoccurs for the serum amyloid A (SAA) protein during theacute-phase response accompanying inflammatory disor-ders such as rheumatoid arthritis, or chronic granuloma-tous infections such as tuberculosis. A 76-residue proteolyticfragment of wild-type SAA can then accumulate, misfold,aggregate and be deposited in the connective tissue of multi-ple organs, including spleen, kidney and liver. Multiplemyeloma is associated with the overproduction by plasmacells of monoclonal immunoglobulins that accumulate andform deposits (as holoproteins and/or proteolytic frag-ments) in the extracellular space of various tissues. Primarysystemic amyloidosis also involves progressive multi-tissuedeposition of immunoglobulin light chains and their frag-ments. In some systemic amyloidoses, the basis for anFolding proteins in fatal waysDennis J. SelkoeCenter for Neurologic Diseases, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA(e-mail: [email protected])Human diseases characterized by insoluble extracellular deposits of proteins have been recognized foralmost two centuries. Such amyloidoses were once thought to represent arcane secondary phenomena ofquestionable pathogenic significance. But it is has now become clear that many different proteins canmisfold and form extracellular or intracellular aggregates that initiate profound cellular dysfunction.Particularly challenging examples of such disorders occur in the post-mitotic environment of the neuron andinclude Alzheimer’s and Parkinson’s diseases. Understanding some of the principles of protein folding hashelped to explain how such diseases arise, with attendant therapeutic insights.© 2003 Nature PublishingGroupincreased concentration of an amyloidogenic protein is a perturba-tion in its clearance. One striking example