Molecular and cellular basis of synaptic dysfunction in the ME7 model of prion disease (TSE highlight)

Bovine spongiform encephalitis (BSE) received wide media attention because of the potential risk to public health from eating infected beef. The infected beef is harmful because it contains an abnormal prion protein which when eaten by a healthy individual causes their own normal prion protein to become abnormal.
Nerve cells of the brain are particularly sensitive to this protein imbalance and when infected with abnormal prion stop working and die. We want to study how disease progression is represented at the level of the susceptible nerve cells. We hypothesize that the different parts of the nerve are not equally sensitive to disease and will investigate if synapses, the point of contact between nerves, are particularly susceptible. Synapses are essential to brain function and their disruption will prevent communication even before nerve cells die. In particular, we will use a mouse model of prion disease to look at nerve cells as they undergo degeneration. Identifying which parts of the nerve are most susceptible should help develop ways of preventing the progression from a sick to a dead nerve. Importantly, the work will help us understand and possibly treat other debilitating brain diseases (e.g. Alzheimer’s) associated with the accumulation of abnormal brain proteins.

Transmissible Spongiform Encephalopathies (TSEs) are fatal progressive neurodegenerative diseases. TSE represent a class of protein misfolding diseases in which the degeneration of neurons is associated with the accumulation of aggregated prion protein (PrP). Disease transmission and neuropathology are triggered by exposure to the distinct aggregating protein conformation(s) of PrP (PrPsc) which convert normal cellular prion protein (PrPc) to cause accumulation of PrPsc conformation(s) to trigger neurodegeneration. Although the transition of PrPc to a disease forming conformation(s) is critical, the precise nature of the PrPsc conformer(s) that trigger disease remain ill-defined. Intrahippocampal injection of brain homogenate derived from murine ME7 scrapie is an established in vivo model of prion induced degeneration (ME7 model). This model highlights distinct phases of dissectible behavioral and anatomical parameters which change over a precise and ordered time course. Indeed, impaired performance in a suite of behavioral tests reveals affective and cognitive dysfunction that precedes obvious neuronal degeneration or PrPsc deposition in the CA1 of the hippocampus. However, the early behavioral dysfunctions correlate with a disorganization of synapses in CA1, which precedes cell death in the CA3, the region containing the cell bodies of the degenerating synapses. Consistent with our own preliminary neurochemical data this raises the hypothesis that synapses are an early target of prion induced degeneration. We will take advantage of the compartmentalized disruption of hippocampal synapses in the ME7 model to investigate the morphology and neurochemistry of this dis-organization. Electron microscopy will be used to investigate the quantity and integrity of sub-synaptic structures in the infected hippocampus during the defined time course of the ME7 model. We will use molecular and morphological investigations to discern to what degree the synaptic dysfunction is independent of the cell bodies found in CA3. In addition proteomics of synaptosomes will be used to define the sub-synaptic structures and molecules that are the targets of the early degenerative events in prion disease. Finally we will take advantage of the observation that early synaptic degeneration occurs in the absence of PrPsc disposition and use proven strategies to better define the PrPsc conformers that trigger disease in vivo. Understanding early events in neuropathogenesis are vital if we are to improve treatment of the degenerative sequelae. These approaches will build on emerging theme in TSE, which pertain to other neuropathologies, and highlight synaptic biochemistry as a pivotal target in neurodegenerative disease.