Topics & Solutions

Historical Background of Neurodegenerative Disease Research

Since its historic description by James Parkinson in 1817, the cause of the shaking palsy, comprised of a triad of tremor at rest, muscular rigidity and slowness of movement, often accompanied by speech difficulties, wasting, mood problems and cognitive changes has been difficult to identify. Parkinson's Disease is very rarely inherited. Parkinson’s interesting description of the disease during the period of the Industrial Revolution has prompted people to speculate that environmental exposure to toxic chemicals precipitates the disease. Exposure to manganese precipitated a Parkinsonian syndrome in miners, which disease also includes schizophreniform behaviors. Natural and synthetic insecticides and herbicides have also been suggested as candidate agents because they precipitate on occasion motoric disturbances in animals and man somewhat akin to Parkinsonism. Other types of Parkinsonism include post encephalitic Parkinsonism as a sequel to influenza pandemic of 1918, Wilson's Disease which is an inherited diseases of copper metabolism and Parkinsonism secondary to strokes, space occupying lesions and drugs.

Parkinson's Disease has aroused medical curiosity three times during the twentieth century. First, following the influenza pandemic of 1917 which was associated with post encephalitic Parkinsonism, secondly, the discovery by Horneykiewicz of the dopamine deficit in the substantia nigra nucleus in the brains of Parkinson's Disease patients occurred in 1960 and subsequently dopamine loss has been replaced by oral levodopa therapy and more latterly with synthetic dopamine mimicing drugs. Thirdly, the occurrence of Parkinsonism in humans in the San Francisco Bay area in 1983 who were exposed to methylphenyltetrahydropyridine (MPTP). MPTP became a very intensely studied and gold standard model of Parkinson's Disease, with a search to understand its chemical actions and for substance(s), which would antagonize it and be useful therapeutics.

It was learnt that MPTP inhibits mitochondrial respiration, in particular NADH component 1 enzyme and that this also occurs in Parkinson’s disease. Further it is apparent that MPTP damages mitochondrial DNA and stimulates a damage-initiating enzyme known as polyADP ribose phosphatase (PARP). Mitochondrial DNA damage also occurs in Parkinson’s disease and Parkinson’s disease is diagnosable at a low threshold of mitochondrial DNA damage.

Alzheimer's Disease is also named after the physician who first described the five main pathological finidings of the disease. Parkinson's, Alzheimer's, and Lou Gehrig's Diseases are interrelated via an environmentally induced disease, which occurred prior to World War II in Guam. The toxin which caused this disease called Guamanian Parkinsonian Dementia, was identified as beta methyl amino alanine (BMAA) and this also became a well-studied model of this disease.

In Alzheimer’s Disease the mitochondrial enzyme cytochrome oxidase is inhibited and mitochondrial DNA damage and deletions also occur.

In the 1980s mitochondrial DNA damage was first recognized as an initiating event in these diseases. Verne Mendel discovered the only available non-toxic means to prevent mitochondrial DNA damage and prevent neurotransmitter loss in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) Parkinsonism. The Company’s active compounds protect mitochondrial DNA as well as having beneficial on other regulatory events in neurodegenerative diseases, including the amyloid plaque deposition, which occurs in Alzheimer's Disease.