The Neurodegeneration Sequence in Prion Diseases: Evidence from Functional, Morphological and Ultrastructural Studies of the GABAergic System

Abstract

Loss of the GABAergic system of neurons has been reported to be the first detectable neuropathological change in prion diseases, which features the accumulation of an aberrant isoform of the prion protein (PrP(Sc)). To determine the timing of GABAergic system dysfunction and degeneration and its relationship to PrP(Sc) accumulation during the course of prion disease in Syrian hamsters, we applied 3 approaches: i) quantifying GABA-immunopositive neurons and their processes by light and electron microscopy to test for selective loss; ii) measuring evoked [3H]-GABA release from synaptosomes to test for functional abnormalities; and iii) determining the kinetics of PrP(Sc) accumulation in subcellular fractions to correlate it with GABAergic dysfunction. At the terminal stages of disease, we found a significant increase in the number of GABA-positive and -negative presynaptic boutons with abnormally aggregated synaptic vesicles. At the same stage, we also found an equal degree of GABA-immunopositive and -immunonegative presynaptic bouton loss. In contrast, GABA-positive neocortical cell bodies increased, based on stereologic estimates in the terminal stage of scrapie. In the context of these abnormalities, evoked release of [3H]-GABA from cortical and thalamic synaptosomes was significantly decreased, which correlated well with the accumulation of PrP(Sc) in synaptosomes and cell membrane fractions.

A γ-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains

“…In earlier studies, we and others demonstrated the initial replication of prions at the site of injection with transport along axons (35,36). In the studies described here, PrP Sc formation was initiated by intrathalamic inoculation of prions, and presumably anterograde axonal transport of PrP Sc occurred along the monosynaptic thalamocortical system of axons that connects the thalamus with the cortex (1,6,37).…”

“…In prion-infected rodents, neurodegeneration begins with the accumulation of PrP Sc in neuronal membranes, followed by dendritic atrophy and loss and finally nerve cell death (1,4,10). During studies on the pathogenesis of experimental scrapie in mice, we found that the release of the Notch-1 intracellular domain transcription factor (NICD) preceded early dendritic atrophy in scrapie-infected mice (4).…”

“…P rion diseases are rapidly progressive, invariably fatal neurodegenerative disorders caused by the accumulation of PrP Sc , the pathogenic isoform of the prion protein (1)(2)(3)(4)(5)(6). A wealth of evidence argues that PrP Sc is the sole component of the infectious prion particle.…”

Cerebral White Matter Disruption in Creutzfeldt-Jakob Disease

“…9,21,22 Animal models of CJD also demonstrate white matter deposition of PrP Sc , astrocytes, and vacuolization, all of which are hallmarks of CJD pathology, as well as damage to myelinated axons. 1,10,[23][24][25][26] Recently, new evidence is accumulating to suggest a fundamental relationship of the prion protein to WM. While predominantly neuronal, PrP C (the nor- mal cellular precursor protein) is also expressed in astrocytes and oligodendrocytes.…”

Baxdeletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease

“…In addition, synaptic disorganization and loss have been described in sporadic and inherited Creutzfeldt-Jakob disease, including cases associated with octapeptide insertions (31). Accumulation of abnormal PrP at presynaptic and postsynaptic sites has been found to precede neuronal dysfunction and death and be associated with loss of synaptic contacts in the CNS of scrapie-infected mice and patients with CreutzfeldtJakob disease (29,(32)(33)(34).…”