Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology

Abstract

Prions have served as pathfinders that reveal many aspects of proteostasis in neurons. The recent realization that several prominent neurodegenerative diseases spread via a prion-like mechanism illuminates new possibilities for diagnostics and therapeutics. Thus, key proteins in Alzheimer Disease and Amyotrophic lateral sclerosis (ALS), including amyloid-β precursor protein, Tau and superoxide dismutase 1 (SOD1), spread to adjacent cells in their misfolded aggregated forms and exhibit template-directed misfolding to induce further misfolding, disruptions to proteostasis and toxicity. Here we invert this comparison to ask what these prion-like diseases can teach us about the broad prion disease class, especially regarding the loss of these key proteins’ function(s) as they misfold and aggregate. We also consider whether functional amyloids might reveal a role for subverted protein function in neurodegenerative disease. Our synthesis identifies SOD1 as an exemplar of protein functions being lost during prion-like protein misfolding, because SOD1 is inherently unstable and loses function in its misfolded disease-associated form. This has under-appreciated parallels amongst the canonical prion diseases, wherein the normally folded prion protein, PrPC, is reduced in abundance in fatal familial insomnia patients and during the preclinical phase in animal models, apparently via proteostatic mechanisms. Thus while template-directed misfolding and infectious properties represent gain-of-function that fascinates proteostasis researchers and defines (is required for) the prion(-like) diseases, loss and subversion of the functions attributed to hallmark proteins in neurodegenerative disease needs to be integrated into design towards effective therapeutics. We propose experiments to uniquely test these ideas.

An ancient conserved role for prion protein in learning and memory

“…Further, our data strongly support the growing list of phenotypes observed in prion loss-of-function models that map with high fidelity onto prion disease symptomology ( Leighton and Allison, 2016 ; Allison et al, 2017 ). Thus, in contradistinction to the simplifying assumption that protein gain-of-function is largely responsible for disease outcomes, we infer that the aetiology of prion diseases likely requires prion protein function to be at least partially lost or subverted on the path to dementia.…”

Prion gene paralogs are dispensable for early zebrafish development and have nonadditive roles in seizure susceptibility

“…Further study of the mechanisms through which prion proteins contribute to neuromast patterning and neurophysiology in the zebrafish will provide new insights into the role of PrP C in neural development and maintenance. Considering the disruption/subversion of the function of PrP C in both prion disease and Alzheimer's disease (1,2), these studies will likely uncover putative therapeutic targets for prion diseases and Alzheimer's disease.…”

“…However, in double prp mutants, this third protein would be expected to be able to compensate for loss of the active prp paralog. It remains to be determined what protein(s) might be at the center of this putative antagonism, although candidates may include molecules such as metabotropic glutamate receptor 5 and APP that are thought to transduce extracellular signals bound to PrP C through to the intracellular compartment (2,8,22,74,75). Identifying commonalities and differences among the functions of zebrafish prp1, prp2, and mammalian Prnp is expected to inspire new hypotheses about the key functions of PrP C and their relevance to the etiology of neurodegeneration.…”

“…Reduced normal cellular prion protein (PrP C ) 3 function(s) are a likely contributor to prion disease progression (despite its loss not being sufficient for disease (1,2)); thus, it is important to understand the normal physiological functions of PrP C to devise effective disease therapies. Furthermore, removal of PrP C is considered a promising therapeutic avenue for prion and Alzheimer's diseases (3,4), and knowing its function is critical to predicting safety and mitigating detrimental effects of treatment.…”

Prionoid Proteins in the Pathogenesis of Neurodegenerative Diseases

“…The specific mechanisms of activity vary between disorders, but they all ultimately lead to the death of a specific set of neurons in the brain. Disentangling the symptoms resulting from loss- or gain-of-function is often difficult, as the major function gained (prionoid protein misfolding) is often accompanied by loss of function (Allison et al, 2017). Leighton and Allison (2016) recently reviewed gain and loss of function mechanisms in AD, HD and ALS.…”