Selective vulnerability to neurodegenerative disease: the curious case of Prion Protein

Abstract

The mechanisms underlying the selective targeting of specific brain regions by different neurodegenerative diseases is one of the most intriguing mysteries in medicine. For example, it is known that Alzheimer’s disease primarily affects parts of the brain that play a role in memory, whereas Parkinson’s disease predominantly affects parts of the brain that are involved in body movement. However, the reasons that other brain regions remain unaffected in these diseases are unknown. A better understanding of the phenomenon of selective vulnerability is required for the development of targeted therapeutic approaches that specifically protect affected neurons, thereby altering the disease course and preventing its progression. Prion diseases are a fascinating group of neurodegenerative diseases because they exhibit a wide phenotypic spectrum caused by different sequence perturbations in a single protein. The possible ways that mutations affecting this protein can cause several distinct neurodegenerative diseases are explored in this Review to highlight the complexity underlying selective vulnerability. The premise of this article is that selective vulnerability is determined by the interaction of specific protein conformers and region-specific microenvironments harboring unique combinations of subcellular components such as metals, chaperones and protein translation machinery. Given the abundance of potential contributory factors in the neurodegenerative process, a better understanding of how these factors interact will provide invaluable insight into disease mechanisms to guide therapeutic discovery.

Transcellular spreading of huntingtin aggregates in theDrosophilabrain

“…Therefore, the only neurons where accumulation of aggregates can be seen in abundance are those that are most resistant to the toxic effects of the aggregates. Whereas the underlying cause of this selective vulnerability remains unknown, some leading ideas include differences in the microenvironment, metabolic activity, and translational machinery between neuronal populations (41,42).…”

Translation of the Prion Protein mRNA Is Robust in Astrocytes but Does Not Amplify during Reactive Astrocytosis in the Mouse Brain

“…That these cells, compared to astrocytes in brain, have easily detectable PrP is difficult to explain but may indicate that astrocytes in culture retain more PrP than those in brain, and may also indicate that conventional cultures of astrocytes are quite different from those in mature brain [59]. While cell type specific protein quality control systems may process PrP differently [11], our results indicate that the differences in PrP levels across different brain regions is at least partially influenced by Prnp ’s differential activity in different cells, consistent with mRNA localization studies [12].…”

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

“…According to this older concept, certain neurons are intrinsically more vulnerable to the underlying pathogenic processes of a disease (such as those that cause the misfolding and aggregation of a certain protein) than others (233,234), perhaps because of their gene expression profiles, and that these vulnerable neurons thus become dysfunctional and structurally abnormal earlier than the others. The pathogenic spread hypothesis tends to emphasize a non-cell-autonomous mechanism of disease, whereas the selective neuronal vulnerability hypothesis tends to emphasize a more cell-autonomous mechanism.…”