Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein

Converging paradigms in neurodegeneration Parkinson's disease and Alzheimer's disease are progressive neurodegenerative diseases with increasing prevalence in our aging populations. Recent evidence suggests that some of the molecular mechanisms involved in the pathology of these diseases have similarities to those observed in infectious prion diseases such as bovine spongiform encephalopathy (mad cow disease). Goedert reviews how the spread of a variety of pathological protein aggregates is involved in neurodegenerative disease. Science, this issue p. 10.1126/science.1255555 BACKGROUND Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common human neurodegenerative diseases. AD is primarily a dementing disease, and PD is a movement disorder. Together, they affect around 50 million people worldwide, with the vast majority of disease cases being sporadic. Their incidence increases with age. Like most neurodegenerative diseases, AD and PD are caused by the aggregation of a small number of proteins, with filament assemblies constituting the end-point of protein aggregation. AD is characterized by the presence of abundant extracellular plaques made of amyloid assemblies of Aβ peptides and intraneuronal inclusions made of assembled tau protein. Some dominantly inherited cases of AD are caused by mutations in the gene encoding the amyloid precursor protein (APP), the cleavage of which gives rise to Aβ. In these cases, dysfunction of APP precedes dysfunction of tau. In contrast, mutations in MAPT, the tau gene, give rise to dominantly inherited frontotemporal dementia and parkinsonism, with abundant tau inclusions in the absence of Aβ plaques. Extrapolation to the much more common sporadic cases of AD has given rise to the amyloid cascade hypothesis, which postulates that Aβ aggregation causes the formation of tau inclusions, synaptic dysfunction, nerve cell death, and brain shrinkage. However, tau inclusions correlate better with cognitive impairment, and Aβ may exert its effects through tau. Strategies targeting the formation of Aβ and tau assemblies are valuable for the development of mechanism-based therapies. Unlike AD, in which two distinct amyloid assemblies are present, PD is characterized by intracellular deposits, Lewy bodies and neurites, both composed of the protein α-synuclein. Dominantly inherited forms of PD are caused by mutations in SNCA, the α-synuclein gene. More than 95% of those diagnosed with PD have Lewy inclusions. ADVANCES For many years, the mechanisms underlying AD and PD were widely believed to be cell-autonomous. This implies that the same molecular events, such as the formation of tau and α-synuclein assemblies, occur independently in a large number of cells in an otherwise healthy brain. Recent findings have suggested instead that non–cell-autonomous processes play an important part in AD and PD. Inclusions are thought to form in a small number of cells and—given enough time and, perhaps, a genetic predisposition—spread in a deterministic manner to distant brain regions. The formation of the first Aβ, tau, and α-synuclein inclusions is probably stochastic, with most seeds being degraded. Distinct molecular conformers of aggregated proteins (or strains) may underlie clinically different diseases. This is reminiscent of human prion diseases, such as Creutzfeldt-Jakob disease (CJD). However, there is reluctance to use the term prion for the inclusions of AD and PD. The main reasons are that in contrast to Kuru and CJD, transmission of AD and PD has not been demonstrated between individuals, and most experimental studies have used transgenic animals that overexpress disease proteins. OUTLOOK The prion concept appears to apply to all human neurodegenerative diseases with abnormal protein assemblies, including AD and PD. This has brought unity to the field and changed the way we think about these diseases. It has been known for some time that a seed can template aggregation of the homologous protein. However, the ability of protein aggregates to spread through the nervous system had previously been underappreciated. At a practical level, the new findings are helping to elucidate the mechanisms underlying disease, which may have therapeutic implications in all cases. It will be important to identify the molecular species of assembled host proteins responsible for propagation and neurotoxicity. A pathological pathway leading from soluble proteins to insoluble filaments. This pathway is at the heart of human neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. The formation of pathological seeds is a rare and energetically unfavourable event, which requires exposure of backbone amide groups and a high protein concentration. Once a seed has formed, single molecules can change shape and join the growing aggregates. Seed addition induces rapid assembly of the soluble protein. Fragmentation generates new seeds, accelerating the formation of aggregates. Filaments represent the endpoints of aggregation. They are typically unbranched, with a diameter of ~10 nm, and can be several micrometers long. This drawing is not to scale. [Adapted from S. K. Fritschi et al., in Proteopathic Seeds and Neurodegenerative Diseases, M. Jucker, Y. Christen Eds. (Springer, Berlin, 2013), pp. 61–69]. The pathological assembly of Aβ, tau, and α-synuclein is at the heart of Alzheimer’s and Parkinson’s diseases. Extracellular deposits of Aβ and intraneuronal tau inclusions define Alzheimer’s disease, whereas intracellular inclusions of α-synuclein make up the Lewy pathology of Parkinson’s disease. Most cases of disease are sporadic, but some are inherited in a dominant manner. Mutations frequently occur in the genes encoding Aβ, tau, and α-synuclein. Overexpression of these mutant proteins can give rise to disease-associated phenotypes. Protein assembly begins in specific regions of the brain during the process of Alzheimer’s and Parkinson’s diseases, from where it spreads to other areas.