Neurodegenerative disorders such as Alzheimer’s, Parkinson’s, Huntington’s, and all forms of prion diseases are characterized by death or degeneration of certain regions of the brain. However, the first noticeable neuropathological symptoms that precede this neuronal death tends to be synaptic dysfunction. As we (MSBS students) remember from the physiology TBL #1, the connectedness and strength of neurons relies strongly on that neuron’s dendritic tree. Just as Dr. Campisi mentioned, a “remapping” of a neuron’s dendritic tree can occur due to a litany of causes. One such cause could be an individual who goes blind and now reads primarily through braille. This individual’s brain region responsible for fingertip sensation will be far more branched and expansive. However the exact opposite can occur: a loss of dendritic branching. This dendritic loss often times occurs as a result of synaptic dysfunction, characterized by abnormal activity at the synapse.
This occurs in prion diseases. Prion diseases are group of diseases whereby the pathogenic disease causing agent is a misfolded variant of the endogenous and normally expressed protein termed Cellular Prion Protein or PrPC. This is a rare group of diseases afflicting about 1 in 1 million individuals worldwide and is characterized by rapidly progressive dementia (1-3 months following first symptoms) ataxia and other neuromuscular symptom and ultimately death (in most cases around 6-8 months from first symptoms). Well known pathologies that are a part of the prion family include mad cow disease, scrapie, Creutzfeldt Jakob disease, fatal familial insomnia, and Kuru. Not much is clear in regards to the mechanisms behind the pathogenesis and neurotoxicity of prion diseases. However, one mechanism was proposed in terms of how prions can cause this synaptic dysfunction that us MSBS students as well as some undergraduate students (hopefully) should understand quite easily.
Without getting into weeds of prion diseases, it is the accumulation of the misfolded variant of the prion protein (termed PrPSc) that is responsible for causing the characteristic effects of prion diseases. Specifically in terms of synaptic dysfunction, these misfolded proteins accumulate in the lipid rafts on the cellular surface of neurons and in so doing displace other proteins to make room for itself. Some of these displaced proteins are Snap-25, syntaxins, and synapsins. It’s been awhile but what important neuronal function would be effected by the removal of these proteins? Exocytosis! Any form of vesicular release really. With decreased exocytosis of neurotransmitters at the synapse we get decreased activity overall at the synapse. This ultimately leads to dendritic atrophy due to the dendrites receiving less and less neuronal stimulus. It is this synaptic dysfunction and dendritic loss that is often responsible for the first noticeable behavioral symptoms in patients suffering from neurodegenerative disorders.
https://pubmed.ncbi.nlm.nih.gov/10842016/
It has always been interesting to me how the brain/body in general has so much plasticity but can also be so susceptible to irregularities! In a study I found by Supattapne et al., (1999) found that the use of polyanimes were effective in eliminating prions from cultured cells. This is interesting as it could potentially reverse or halt the effects of neurodegenerative diseases. I know that there has been a lot of research recently looking at neurodegenerative diseases and this may be interesting to see if it could be a potential effective therapy.
ReplyDeleteSupattapone, S., Nguyen, H. O. B., Cohen, F. E., Prusiner, S. B., & Scott, M. R. (1999). Elimination of prions by branched polyamines and implications for therapeutics. Proceedings of the National Academy of Sciences, 96(25), 14529-14534.