By Helen Luojia Zhang
Neuronal dysfunction and brain damage due to accumulation and aggregation of misfolding proteins is a hallmark event in neurodegenerative diseases (Soto & Pritzkow, 2018). Although many different proteins are involved in different neurodegenerative disorders, the process of protein misfolding and aggregation remains similar. It has been suggested that misfolded protein aggregates can self-propagate and spread between cells in a prion-like manner. The prion hypothesis states that misfolded proteins can act as infectious agents that template the misfolding and aggregation of healthy proteins to transmit a disease (Soto, 2011). This has profound influence for understanding the mechanisms underlying the initiation and progression of neurodegenerative diseases, as well as for the development of diagnostics and effective therapies.
The nature of the infectious scrapie agent was heavily debated for several decades until a breakthrough came in the 1980s when Prusiner SB discovered novel proteinaceous infectious particles (prions) as the causative agent of scrapie (Prusiner, 1982). He analysed the brain extract of animals inoculated with infected brain tissues and found out that the infectivity of these extracts was not disrupted by treatments that destroy nucleic acids. This leads to the prion hypothesis that the infectious scrapie agent is proteinaceous, which can replicate and propagate itself without nucleic acids. The infectious agent was subsequently identified to be scrapie PrP (PrPSc), which is a neurotoxic conformational variant of normal cellular PrP (PrPC). PrPSc propagates by recruiting the PrPC and stimulating its conformational conversion into the disease-causing isoform (PrPSc). In addition to scrapie, a series of other neurodegenerative diseases such as bovine spongiform encephalopathy (BSE), kuru and Creutzfeldt–Jakob disease (CJD) also share prions as the causative agent, which are collectively called prion diseases (Geschwind, 2015).
The concept of protein induced protein conformational change and its propagation has been extended to other neurodegenerative diseases, including Alzheimer’s Disease (AD) and Parkinson’s disease (PD), the two most common neurodegenerative disorders. Alzheimer’s is typically characterized by cognitive impairment such as loss of memory, mood changes and, more seriously, difficulties in eating and sleeping. Extracellular deposition of amyloid plaques due to accumulating misfolded amyloid β protein (Αβ), as well as neurofibrillary tangles (NFTs) due to abnormally aggregating hyperphosphorylated tau protein inside cells are two major pathological features of AD (Scheltens et al., 2016). Patients with PD primarily have motor symptoms, including shaking, rigidity and akinesia. The primary cause for these symptoms is the death of dopamine neurons, which causes the loss of dopamine signalling in the brain, leading to severe motor symptoms (Radhakrishnan & Goyal, 2018). Deposition of Lewy bodies due to overproduction and accumulation of α-synuclein was identified as the prominent pathological hallmark of Parkinson’s disease.
Back in the 1950s, thousands of children with growth disorder were injected with growth hormone derived from pituitary glands of human cadavers. This treatment was forced to cease in 1985 when a few patients who received the injection had developed CJD due to the prion-contaminated growth hormone. Unexpectedly, in addition to abnormal prion proteins, Aβ plaques were also found in the grey matter of four patients (Huynh & Holtzman, 2018). This suggests Aβ seed can retain its pathological activity for a long time and can potentially be transmitted through medical procedures. Furthermore, the patient receiving a transplant of foetus dopamine neurons shows Lewy bodies in both the host substantia nigra and the transplant, suggesting possible host-to-graft spreading of Lewy pathology in Parkinson’s disease, which act as additional evidence for the existence of prion-like mechanisms. (Li et al., 2008)
Later experiments on animal models have further proved the seeding activities of misfolded amyloid-beta proteins and alpha-synuclein. Aβ-containing brain extracts from humans with Alzheimer’s were injected into the brain of transgenic mice, which had induced numerous Aβ deposits in the brain of mice after four months, suggesting a prion-like transmission mechanism of Aβ (Stöhr et al., 2012). Similarly, focal injection of α-synuclein fibrils into wildtype mice caused spread of α-synuclein pathology across the brain, including dopamine neurons (Luk et al., 2012). Whereas injecting α-synuclein fibrils into α-synuclein knockout mice did not cause spread of the pathology. This suggests that recruitment of endogenous α-synuclein is essential for the pathology, providing additional evidence for prion-like mechanism of spreading and propagation of α-synuclein.
Distribution of amyloid-β, tau and α-synuclein inclusions were analysed in the brains of patients died at different stages of PD and AD, which indicated that the misfolded proteins spread across the brain along anatomically connected networks in a prion-like manner (Goedert, Clavaguera & Tolnay, 2010). However, how prions spread from cell-to-cell is not yet fully understood. Interneuronal spreading of Aβ, tau and α-synuclein aggregates requires their release into the extracellular space and uptake by connected cells. Potential mechanisms underlying the intercellular transfer of prion-like misfolded proteins include direct diffusion through extracellular space and transmission via nanotubes or via exosomes. (Goedert, Eisenberg & Crowther, 2017) An open and controversial issue is whether spreading of protein misfolding is equivalent to spreading of disease. In some cases, the pathological induction is restricted to the accumulation of protein aggregates, and in others it is accompanied by tissue damage and clinical signs typical of the disease. The prion-like transmission mechanism has raised the concern that misfolded proteins could potentially act as infectious agents to transmit the disease among individuals under natural conditions. However, there is no clear evidence to suggest that Alzheimer’s disease and Parkinson’s disease can transfer between individuals.
The prion-like aspect of these neurovegetative diseases may provide new opportunities for therapeutic intervention at different stages of prion formation and spreading. For instance, drugs that inhibit uptake or release of misfolded protein aggregates could block intercellular transmission, and thereby potentially inhibiting prion propagation. Drugs that inhibit misfolding protein aggregation or facilitate the removal of oligomeric seed could also serve as potential therapy. Understanding the molecular mechanism of prion replication and propagation might be the key to treat a whole range of neurodegenerative diseases.
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