Prion-Like Characteristics of Polyglutamine-Containing Proteins

Abstract

Transmissible spongiform encephalopathies are infectious neurodegenerative diseases caused by the conversion of prion protein (PrP) into a self-replicating conformation that spreads via templated conversion of natively folded PrP molecules within or between cells. Recent studies provide compelling evidence that prion-like behavior is a general property of most protein aggregates associated with neurodegenerative diseases. Many of these disorders are associated with spontaneous protein aggregation, but genetic mutations can increase the aggregation propensity of specific proteins, including expansion of polyglutamine (polyQ) tracts, which is causative of nine inherited neurodegenerative diseases. Aggregates formed by polyQ-expanded huntingtin (Htt) in Huntington's disease can transfer between cells and seed the aggregation of cytoplasmic wild-type Htt in a prion-like manner. Additionally, prion-like properties of glutamine-rich proteins underlie nonpathological processes in yeast and higher eukaryotes. Here, we review current evidence supporting prion-like characteristics of polyQ and glutamine-rich proteins.

Figure 1.

Polyglutamine (PolyQ)-containing proteins implicated in inherited neurodegenerative diseases. The domain organizations of nine proteins associated with inherited neurodegenerative diseases caused by polyQ expansion are shown. PolyQ tracts are shown in black, with reported ranges for wild-type (WT) (green) and mutant (red) lengths indicated underneath. HEAT, Repeats found in huntingtin, elongation factor 3, protein phosphatase 2A, and TOR1; SCA, spinocerebellar ataxia; AXH, ataxin-1 and HMG box-containing protein 1 domain; UIM, ubiquitin interacting motif; CACNA1A, Cav2.1 P/Q voltage-dependent calcium channel; SCA7, ataxin-7 atypical zinc finger; TBP, TATA box-binding protein.

Figure 2.

Prion-like transmission of mutant huntingtin (Htt) and polyQ aggregates. (A) Monomeric mutant Htt proteins containing a polyQ tract of greater than 37 glutamines will self-assemble into amyloid when a critical concentration has been achieved (top). Monomeric WT Htt proteins containing 36 or fewer glutamines do not form aggregates unless nucleated by a preformed Htt aggregate seed (bottom). (B) Aggregation kinetics for mutant Htt (purple line), WT Htt (green line), and WT Htt after addition of an aggregate mutant Htt seed (dotted green line). (C) Purified mutant Htt or polyQ aggregates nucleate the aggregation of WT Htt expressed in the cytoplasm of cultured mammalian cells. (D) Mutant Htt aggregates can transfer between individual co-cultured cells, before or after cell lysis (indicated by dotted cell membrane), and nucleate the aggregation of cytoplasmic WT Htt proteins in recipient cells. (E) In a Drosophila model of Huntington’s disease (HD), mutant Htt aggregates formed in presynaptic olfactory receptor neurons transfer to neighboring phagocytic glia and nucleate the aggregation of cytoplasmic WT Htt in a process that requires the phagocytic receptor, Draper, and its associated engulfment machinery. Whether cytoplasmic entry of neuronal Htt aggregates occurs at the plasma membrane during phagocytic engulfment or after formation of a sealed nascent phagosome is not yet clear.