Prion Protein
The normal prion protein isoform (PrPc) is a naturally occurring cellular protein expressed in all tissue of the human body with highest levels expressed in the central nervous system (CNS). Functions include:
An abnormal isoform PrPsc is capable of inducing prion diseases such as Transmissible Spongiform Encephalopathies (TSEs). After initial infection and prion replication, prions migrate from the peripheral regions of the host to the CNS, culminating in a fatal neurodegenerative process.
More commonly, the peripheral entry point for PrPsc is the gastro-intestinal tract (GIT). Haematopoietic cells, lymphoid cells and secondary lymphoid organs play a critical role to facilitate initial site of replication and transport to the CNS via sympathetic (Splanchic) or parasympathetic (Vagus) fibres of the enteric nervous system (ENS).
Involved in this process are exosomes, small membranous vesicles secreted by a number of cells including neurons. Ultimately they play an important role in cell to cell spread, removal of unwanted protein and transfer of pathogens between cells.
- Immunoregulation
- Signal transduction
- Synaptic transmission
- Protect against or induce apoptosis
An abnormal isoform PrPsc is capable of inducing prion diseases such as Transmissible Spongiform Encephalopathies (TSEs). After initial infection and prion replication, prions migrate from the peripheral regions of the host to the CNS, culminating in a fatal neurodegenerative process.
More commonly, the peripheral entry point for PrPsc is the gastro-intestinal tract (GIT). Haematopoietic cells, lymphoid cells and secondary lymphoid organs play a critical role to facilitate initial site of replication and transport to the CNS via sympathetic (Splanchic) or parasympathetic (Vagus) fibres of the enteric nervous system (ENS).
Involved in this process are exosomes, small membranous vesicles secreted by a number of cells including neurons. Ultimately they play an important role in cell to cell spread, removal of unwanted protein and transfer of pathogens between cells.
Involvement in Neurodegenerative Diseases (ND's)
- PrPc can function as a cell surface receptor for toxic beta amyloid (AB) oligomers and this interaction seems to be critical for AB-oligomer mediated disruption of synaptic function.
- Exosomes are involved in the processing of amyloid precursor protein (APP) which is associated with Alzheimer's Disease (AD). Exosomes have been shown to contain full length APP and its cleaved products including AB.
- Exosomes may provide a means of intracellular to extracellular transport of such proteins during the pathogenesis of AD as well as cell to cell spread.
- Exosomal markers have been shown to be enriched in amyloid plaques in the brains of mice and post mortem samples of human AD patients. This again indicates that the trafficking of AB aggregates during disease progression may partly rely on similar transport mechanisms seen in prion diseases.
Therapeutic Implications
It has been hypothesized that the GIT may represent an entry point for altered proteins, such has been demonstrated in prion diseases and now postulated for other neurodegenerative diseases such as AD.
The hypothesis of transmissibility of ND's could alter future therapeutic approaches.
Combining cell substitution therapy (stem cells) with treatments that block cell to cell spread could aid in limiting the recruitment of stem cells in the spread of neurodegeneration.
Furthermore, such novel treatments may limit the actual spread of misfolded proteins especially during early stages of the disease prior to permanent pathological changes.
The hypothesis of transmissibility of ND's could alter future therapeutic approaches.
Combining cell substitution therapy (stem cells) with treatments that block cell to cell spread could aid in limiting the recruitment of stem cells in the spread of neurodegeneration.
Furthermore, such novel treatments may limit the actual spread of misfolded proteins especially during early stages of the disease prior to permanent pathological changes.