Prion protein post-translational modifications modulate heparan sulfate binding and limit aggregate size in prion disease.

Prion protein post-translational modifications modulate heparan sulfate binding and limit aggregate size in prion disease. Neurobiol Dis. 2020 May 23;:104955 Authors: Callender JA, Sevillano AM, Soldau K, Kurt TD, Schumann T, Pizzo DP, Altmeppen H, Glatzel M, Esko JD, Sigurdson CJ Abstract Many aggregation-prone proteins linked to neurodegenerative disease are post-translationally modified during their biogenesis. In vivo pathogenesis studies have suggested that the presence of post-translational modifications can shift the aggregate assembly pathway and profoundly alter the disease phenotype. In prion disease, the N-linked glycans and GPI-anchor on the prion protein (PrP) impair fibril assembly. However, the relevance of the two glycans to aggregate structure and disease progression remains unclear. Here we show that prion-infected knockin mice expressing an additional PrP glycan (tri-glycosylated PrP) develop new plaque-like deposits on neuronal cell membranes, along the subarachnoid space, and periventricularly, suggestive of high prion mobility and transit through the interstitial fluid. The plaque-like deposits were largely non-congophilic and composed of full length, uncleaved PrP, indicating retention of the glycophosphatidylinositol (GPI) anchor. Prion aggregates sedimented in low density fractions following ultracentrifugation, consistent with oligomers, and bound low levels of heparan sulfate similar to other predominantly ...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
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