Originally Posted on Journal of Neurology & Translational Neuroscience | 19 August 2013
Prion Proteins: Molecular Footprint Found in Brain Diseases. Tech talk curated from a scholarly paper, this blog is for those of you wearing white lab-coats and pen pocket protectors! 👩🔬👨🔬
Brain diseases are chronic and often fatal illnesses that affect the most precious qualities of human beings. This disease group includes Alzheimer’s disease, Parkinson’s disease, and other rarer disorders such as Huntington’s disease, spinocerebellar ataxia, and prion diseases (also called transmissible spongiform encephalopathies), and amyotrophic lateral sclerosis. Despite the diversity in clinical manifestation, neurodegenerative diseases share many common features, including their relationship to aging, the progressive and chronic nature of the disease, the extensive but localized loss of neurons and synaptic abnormalities, and the presence of cerebral deposits of prion proteins aggregates.
Over the past 20 years, research has provided compelling evidence for these prion-protein aggregates’ key role in neurodegenerative disorders. Each neurodegenerative disease is associated with protein folding abnormalities, leading to oligomers and large aggregates composed of a different protein. In this article, I outline the main pending questions related to prion-protein aggregates in neurodegenerative diseases.
Is prion-protein aggregates the cause of neurodegenerative diseases?
Despite compelling evidence from genetic, biochemical, and neuropathological analysis and studies with animal models, it remains not completely proven that the accumulation of misfolded protein aggregates is the underlying cause of the disease. The definitive proof will likely only be obtained if the disease can be successfully treated or prevented by eliminating misfolded aggregates.
What is the identity and structure of the toxic form of prion-protein aggregates?
The process of protein misfolding and aggregation results in forming a continuum of particles of different sizes and structures, ranging from dimmers to very large fibrils. The majority of the evidence points that small, soluble oligomers are the most neurotoxic species in the brain. However, many different aggregates may likely be toxic, perhaps by distinct mechanisms.
Moreover, it seems clear that the various particles are in a dynamic equilibrium among each other, further complicating the study of their specific properties. The heterogeneity, interconversion, insolubility, and non-crystalline nature of misfolded aggregates impose enormous complications for elucidating these molecules’ atomic-resolution structures.
Nevertheless, much progress has been made in recent years, especially using short peptide models of protein aggregates.
How prion-protein aggregates damage neurons?
It was initially thought that neuronal apoptosis was the most important problem in neurodegeneration, however recent evidence from different diseases suggests that extensive neuronal death may not be the initial cause of the disease. Indeed, clinical symptoms have been clearly described before a significant neuronal loss, and a better temporal and topographic correlation is found with synaptic dysfunction.
Although the mechanism of neurotoxicity is an extensively studied topic and many different hypotheses have been proposed, it is still unclear which of the different models operates in vivo in the human brain. Some of the pathways proposed include:
- Activation of signal transduction pathways leading to neuronal dysfunction;
- Recruitment of cellular factors essential for neuronal functioning;
- Membrane disruption and depolarization mediated by pore formation;
- Impairment of the protein homeostasis machinery in the cell;
- Extensive oxidative and endoplasmic reticulum stress;
- Induction of mitochondrial dysfunction; and
- Triggering a chronic inflammatory reaction in the brain.