Strains of Pathological Protein Aggregates in Neurodegenerative Diseases

Abstract

The presence of protein aggregates in the brain is a hallmark of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Considerable evidence has revealed that the pathological protein aggregates in many neurodegenerative diseases are able to self-propagate, which may enable pathology to spread from cell-to-cell within the brain. This property is reminiscent of what occurs in prion diseases such as Creutzfeldt-Jakob disease. A widely recognized feature of prion disorders is the existence of distinct strains of prions, which are thought to represent unique protein aggregate structures. A number of recent studies have pointed to the existence of strains of protein aggregates in other, more common neurodegenerative illnesses such as AD, PD, and related disorders. In this review, we outline the pathobiology of prion strains and discuss how the concept of protein aggregate strains may help to explain the heterogeneity inherent to many human neurodegenerative disorders.

Keywords: Alzheimer’s disease; Aβ; Creutzfeldt-Jakob disease; Parkinson’s disease; Prion; SOD1; amyotrophic lateral sclerosis; evolution; strain; structure; tau; transmission; yeast prion; α-synuclein.

Figure 1. Evidence for the existence of prion strains from transmission studies using inbred mice

The relative incubation periods for the prion strains Me7 and 22A depend on the sinc genotype of the mouse line. C57BL/6 mice are homozygous for the s7 sinc allele whereas VM mice are homozygous for the p7 allele. The presence of distinct incubation periods for different prion isolates in the same line of inbred mice provided early evidence for the existence of prion strains.

Figure 2. Generation and characterization of the HY and DY prion strains

Repeated passaging of the Stetsonville transmissible mink encephalopathy (TME) isolate in Syrian golden hamsters led to the emerge of the HY and DY strains, which exhibited incubation periods of 65 or 168 days, respectively. A representative PrP immunoblot of HY (left) and DY (right) strains following limited PK digestion (+) is also shown. Note the difference in electrophoretic mobility and sensitivity to extended PK digestion (++) between the two strains (represented by band shading). HY and DY strains have a similar ratio of the three PrP^Sc glycoforms.

Figure 3. Strains of PrPSc in sporadic CJD patients

(A) The three possible codon 129 PRNP genotypes. (B) Classification of sCJD strains according to the “Gambetti” system. Immunoblot profile showing Type 1 (~21 kDa) and Type 2 (~19 kDa) PrP^Sc as defined by the size of the PK-resistant PrP^Sc fragments. In this system, six subtypes of sCJD are defined according to the PrP^Sc type and the codon 129 genotype: MM1, MV1, VV1, MM2, MV2, and VV2. (C) Classification of sCJD strains according to the “London” system. In this system, three distinct sizes of PK-resistant PrP^Sc are defined (Types 1, 2, and 3). In combination with the codon 129 genotype, six subtypes of sCJD are commonly observed: 1MM, 2MM, 2MV, 2VV, 3MV, and 3VV. (D) PrP^Sc pathology in the frontal cortex from an sCJD patient with the MM1 subtype showing diffuse deposits in a punctate or “synaptic” staining pattern. (E) A PrP^Sc plaque in the frontal cortex from an sCJD patient with the MV2 subtype.

Figure 4. The cloud and deformed templating hypotheses for prion strain evolution

(A) In the cloud hypothesis, there is pre-existing conformational heterogeneity within a prion strain. A single dominant sub-strain (red circles) is responsible for the bulk properties of the strain in a given environment. If the strain is shifted to a new environment (such as the presence of an anti-prion drug), a minor sub-strain (blue squares) that is more suited to the new conditions may emerge as the new dominant conformer, resulting in the “evolution” of the prion strain. (B) In the deformed templating hypothesis, the templated replication of a single conformational state (red circles) may occasionally be imperfect, leading to production of a conformationally distinct molecule (blue square). If this new isoform has a selective advantage in the current replication environment, it may eventually take over and become the dominant conformer.