BackgroundPrP systemic amyloidosis is increasingly recognized as a novel inherited prion disease (IPD) syndrome caused by PRNP C-terminal truncating mutations. As well as systemic manifestations they cause gradually progressive cognitive impairment with neurofibrillary tangle pathology which can be mistaken for Alzheimer's disease (AD).ObjectiveWe describe the clinical, biomarker and neuropathological features of a novel frameshift mutation of PRNP resulting in protein truncation at codon 157.MethodsThe clinical phenotype and biomarker findings, including plasma biomarkers measured using Single Molecule Array (SiMOA) technology are reported for affected living individuals, with neuropathological examination available for the index case.ResultsThe Y157X PRNP mutation has resulted in a phenotype of gradually progressive cognitive decline, peripheral sensory and autonomic polyneuropathy, and gastrointestinal symptoms, with one case presenting with recurrent episodes of nausea, vomiting and electrolyte derangement requiring intensive care unit admission. Plasma biomarkers revealed an AD-like pattern with raised neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and phospho-tau 181 (P-tau 181) in affected individuals. On neuropathological examination there was PrP-cerebral amyloid angiopathy (CAA) and neurofibrillary tau pathology.ConclusionsWe present the clinical, biomarker and pathological findings on investigation of this family and provide further evidence for the association of truncation mutations with PrP systemic amyloidosis.

Truncating mutations in PRNP have been associated with heterogeneous phenotypes ranging from chronic diarrhea and neuropathy to dementia, either rapidly or slowly progressive. We identified novel PRNP stop-codon mutations (p.Y163X, p.Y169X) in two Italian kindreds. Disease typically presented in the third or fourth decade with progressive autonomic failure and diarrhea. Moreover, one proband (p.Y163X) developed late cognitive decline, whereas some of his relatives presented with isolated cognitive and psychiatric symptoms. Our results strengthen the link between PRNP truncating mutations and systemic abnormal PrP deposition and support a wider application of PRNP screening to include unsolved cases of familial autonomic neuropathy.

Alzheimer's disease amyloid-β (Aβ) oligomers are synaptotoxic, inappropriately increasing extracellular glutamate concentration and glutamate receptor activation to thereby rapidly disrupt synaptic plasticity. Thus, acutely promoting brain glutamate homeostasis with a blood-based scavenging system, glutamate-oxaloacetate transaminase (GOT), and blocking metabotropic glutamate 5 (mGlu5) receptor or its co-receptor cellular prion protein (PrP), prevent the acute inhibition of long-term potentiation (LTP) by exogenous Aβ. Here, we evaluated the time course of the effects of such interventions in the persistent disruptive effects of Aβ oligomers, either exogenously injected in wild type rats or endogenously generated in transgenic rats that model Alzheimer's disease amyloidosis. We report that repeated, but not acute, systemic administration of recombinant GOT type 1, with or without the glutamate co-substrate oxaloacetate, reversed the persistent deleterious effect of exogenous Aβ on synaptic plasticity. Moreover, similar repetitive treatment reversibly abrogated the inhibition of LTP monitored longitudinally in freely behaving transgenic rats. Remarkably, brief repeated treatment with an mGlu5 receptor antagonist, basimglurant, or an antibody that prevents Aβ oligomer binding to PrP, ICSM35, also had similar reversible ameliorative effects in the transgenic rat model. Overall, the present findings support the ongoing development of therapeutics for early Alzheimer's disease based on these complementary approaches.

Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting several mammalian species. Its causative agent, disease-associated prion protein (PrPd), is a self-propagating β-sheet rich aberrant conformation of the cellular prion protein (PrPC) with neurotoxic and aggregation-prone properties, capable of inducing misfolding of PrPC molecules. PrPd is the major constituent of prions and, most importantly, is the first known example of a protein with infectious attributes. It has been suggested that similar molecular mechanisms could be shared by other proteins implicated in diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or systemic amyloidoses. Accordingly, several terms have been proposed to collectively group all these disorders. Through the stringent evaluation of those aspects that characterise TSE-causing prions, in particular propagation and spread, strain variability or transmissibility, we will discuss whether terms such as "prion", "prion-like", "prionoid" or "propagon" can be used when referring to the aetiological agents of the above other disorders. Moreover, it will also be discussed whether the term "infectious", which defines a prion essential trait, is currently misused when referring to the other misfolded proteins.

Prion diseases are typically recognized as rapidly progressive dementing illnesses that also feature myoclonus and cerebellar ataxia. Several families have now been described with a late-onset hereditary sensory and autonomic neuropathy caused by truncation of prion protein (PrP), and associated with systemic amyloidosis, which was a profoundly unexpected phenotype. The chronic symptoms of this disorder, termed PrP systemic amyloidosis, can be very disabling, and are comparable to familial amyloid polyneuropathy (FAP) caused by transthyretin mutations. Patients require symptomatic therapies directed towards control of nausea, diarrhoea, incontinence, neuropathic pain and postural hypotension. Although the potential transmissibility of this new prion disease is probably extremely low, we advocate PrP gene analysis before biopsy in the investigation of peripheral and autonomic neuropathies, or for patients with unexplained diarrhoea and neuropathy. Prion diseases and the FAPs both display prominent effects of mutation type on clinical presentation and patterns of pathology-a fascinating but unexplained observation. Several neurodegenerative diseases associated with central protein misfolding, such as Huntington and Parkinson diseases, also have under-recognized peripheral components. Most of the familial amyloidoses can be explained by known gene mutations, but amino acid variants in proteins involved in other central neurodegenerative diseases might direct the initial pathology to the periphery.