Loss of PIKfyve drives the spongiform degeneration in prion diseases

Brain-matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here we report that prion infection and prion-mimetic antibodies deplete the phosphatidylinositol kinase PIKfyve in mouse brains, cultured cells, organotypic brain slices, and in brains of Creutzfeldt-Jakob Disease victims. We found that PIKfyve, an inositol kinase involved endolysosomal maturation, is acylated by zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and destabilization. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion-infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P2, suppressed prion-induced vacuolation. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.

Parkinsonism Associated with Pathological 123I-FP-CIT SPECT (DaTSCAN) Results as the Initial Manifestation of Sporadic Creutzfeldt-Jakob Disease

Sporadic Creutzfeldt-Jakob disease (sCJD) is a type of progressive, subacute encephalopathy associated with spongiform degeneration of the central nervous system. sCJD includes a broad and heterogeneous spectrum of clinical variants, but extrapyramidal symptoms and signs at disease onset were rarely reported. We describe a case of unilateral parkinsonism associated with pathological 123I-ioflupane SPECT (DaTSCAN) results as the initial manifestation of M129V subtype sCJD patient. To the best of our knowledge, only 2 cases of Creutzfeldt-Jakob disease demonstrating nigrostriatal dopaminergic deficits in vivo using DaTSCAN have been published in the literature.

Progressive accumulation of the abnormal conformer of the prion protein and spongiform encephalopathy in the obex of nonsymptomatic and symptomatic Rocky Mountain elk (Cervus elaphus nelsoni) with chronic wasting disease

The purpose of our study was to describe the progressive accumulation of the abnormal conformer of the prion protein (PrPCWD) and spongiform degeneration in a single section of brain stem in Rocky Mountain elk ( Cervus elaphus nelsoni) with chronic wasting disease (CWD). A section of obex from 85 CWD-positive elk was scored using the presence and abundance of PrPCWD immunoreactivity and spongiform degeneration in 10 nuclear regions and the presence and abundance of PrPCWD in 10 axonal tracts, the subependymal area of the fourth ventricle, and the thin subpial astrocytic layer (glial limitans). Data was placed in a formula to generate an overall obex score. Data suggests that PrPCWD immunoreactivity and spongiform degeneration has a unique and relatively consistent pattern of progression throughout a section of obex. This scoring technique utilizing a single section of obex may prove useful in future work for estimating the presence and abundance of PrPCWD in peripheral tissues and the nervous system in elk with CWD.

Complex proteinopathy with accumulations of prion protein, hyperphosphorylated tau, α-synuclein and ubiquitin in experimental bovine spongiform encephalopathy of monkeys

Proteins aggregate in several slowly progressive neurodegenerative diseases called ‘proteinopathies’. Studies with cell cultures and transgenic mice overexpressing mutated proteins suggested that aggregates of one protein induced misfolding and aggregation of other proteins as well – a possible common mechanism for some neurodegenerative diseases. However, most proteinopathies are ‘sporadic’, without gene mutation or overexpression. Thus, proteinopathies in WT animals genetically close to humans might be informative. Squirrel monkeys infected with the classical bovine spongiform encephalopathy agent developed an encephalopathy resembling variant Creutzfeldt–Jakob disease with accumulations not only of abnormal prion protein (PrPTSE), but also three other proteins: hyperphosphorylated tau (p-tau), α-synuclein and ubiquitin; β-amyloid protein (Aβ) did not accumulate. Severity of brain lesions correlated with spongiform degeneration. No amyloid was detected. These results suggested that PrPTSE enhanced formation of p-tau and aggregation of α-synuclein and ubiquitin, but not Aβ, providing a new experimental model for neurodegenerative diseases associated with complex proteinopathies.

Prion Strain Targeting Independent of Strain-Specific Neuronal Tropism

ABSTRACT While neuropathological features that define prion strains include spongiform degeneration and deposition patterns of PrPSc, the underlying mechanism for the strain-specific differences in PrPSc targeting is not known. To investigate prion strain targeting, we inoculated hamsters in the sciatic nerve with either the hyper (HY) or drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent. Both TME strains were initially retrogradely transported in the central nervous system (CNS) exclusively by four descending motor tracts. The locations of HY and DY PrPSc deposition were identical throughout the majority of the incubation period. However, differences in PrPSc deposition between these strains were observed upon development of clinical disease. The differences observed were unlikely to be due to strain-specific neuronal tropism, since comparison of PrPSc deposition patterns by different routes of infection indicated that all brain areas were susceptible to prion infection by both TME strains. These findings suggest that prion transport and differential susceptibility to prion infection are not solely responsible for prion strain targeting. The data suggest that differences in PrPSc distribution between strains during clinical disease are due to differences in the length of time that PrPSc has to spread in the CNS before the host succumbs to disease.