More Brain Points

Limiting Neurodegeneration in Parkinson’s Disease

Parkinson’s disease is a neurodegenerative disorder resulting in the loss of dopamine cells in the substantia nigra, which is responsible for reward and movement in the brain. Past research has incorporated L-DOPA, a dopamine precursor, that is used to increase dopamine levels within the substantia nigra and also slow the progression of stage one Parkinson’s disease. Researcher Ben Yang has a different approach in his research paper review, Calcium, Cellular Aging, and Selective Neuronal Vulnerability in Parkinson’s Disease. He believes that calcium entry into the cell through the L-type calcium Cav 1.3 channel causes oxidative stress in the mitochondria, which in turn create reactive oxygen species that trigger apoptosis in mitochondrial cells (Yang). These reactive oxygen species are also responsible for the dampening of ATP synthase and the mutations in mitochondrial DNA. When too much calcium enters the cytoplasm, it can create an aggregation of Lewy bodies within the endoplasmic reticulum indirectly or within the mitochondria directly. This aggregation of alpha-synuclein proteins (Lewy bodies) prevent the endoplasmic reticulum from undergoing proteostasis and restrict the mitochondria from utilizing energy efficiently (Yang). Yang’s solution to restrict the amount of calcium influx within the cell is to apply a hypertensive drug called isradipine, which also blocks calcium channels. Blocking calcium channels increases mitochondrial density in substantia nigra neurons, which creates a lower turnover in dopamine cells, causing dopamine neurons to age at a slower rate. Isradipine allows the substantia nigra mitochondria to produce less energy expenditure and prevents the formation of reactive oxygen species.

An article from ScienceDaily that ties in with Yang’s research, identifies the alpha-synuclein protein formation in brain cells and a way to block their action in the mammalian brain (John Hopkins Medicine). Ted Dawson, the director of Cell Engineering at John Hopkins School of Medicine, initially published evidence of alpha-synuclein spreading from areas of lower brain structures including movement to areas of higher reasoning and memory function. Building from this aggregation process, Dawson and his research team cultured human brain cancer cells that prevented the alpha-synuclein from entering the cell. The team then added genes to the transmembrane receptors of these cancer cells to see which genes let in the aggregates. Specifically, the transmembrane receptor called LAG3 bound to the alpha-synuclein aggregates (John Hopkins Medicine). The team then created knockout mice that lacked the LAG3 protein receptor and injected them with alpha-synuclein aggregates and sure enough, the neurodegeneration of dopamine neurons was limited by the mice antibodies. The mouse antibodies blocking alpha-synuclein aggregation had similar effects in cultured cancerous human cells and the antibodies are being tested in clinical trials. Thus, the blocking of LAG3 protein can possibly slow the progression of Parkinson’s in humans and be incorporated in chemotherapy, if the antibodies are approved in clinical trials. It seems that Ben Yang’s proposition of isradipine application to block L-type calcium channels aids in the durability of mitochondrial substantia nigra cells. Substantia nigra cells could then use energy in the form of ATP more efficiently and slow the formation of reactive oxygen species. Dawson and his John Hopkins research team’s proposal could possibly eliminate the formation of alpha synuclein aggregate. Both findings can play a part in regulating the neurodegeneration of dopamine neurons in substantia nigra cells.

Works Cited

Johns Hopkins Medicine. "New treatment strategy could cut Parkinson's disease off at the pass."            ScienceDaily. ScienceDaily, 29 September 2016.                       <www.sciencedaily.com/releases/2016/09/160929142756.htm>.

Ben Yang’s research review:            https://luc.app.box.com/v/neuroscienceseminar/1/5783518889/93009542353/1

Journal Reference:

Ted M. Dawson et al. Pathological α-synuclein transmission initiated by binding lymphocyte-  activation gene 3. Science, September 2016 DOI:10.1126/science.aah3374