Parkinson’s Disease: Causes

Pathogenesis (disease development)

About 80% of PD cases are idiopathic, meaning the cause is unknown. Experimental studies raise the suspicion that PD, similar to Creutzfelt-Jakob disease, is caused by the spread of infectious proteins in the brain (prion disease). In the course of the disease, neurons of the substantia nigra (nuclear complex in the area of the mesencephalon (midbrain), which is characterized by a high intracellular content of iron and melanin) die, resulting in a deficiency of dopamine (biogenic amine from the group of catecholamines; an important neurotransmitter). The affected cells show the so-called Lewi bodies as a typical change. The lack of dopamine in this area leads to the symptoms and complaints, since the coordination of voluntary and involuntary movements is significantly controlled in the substantia nigra. In healthy humans, there is a balance between the transmitters dopamine and acetylcholine (biogenic amine; neurotransmitter that plays a central role in the regulation of many bodily processes). The lack of dopamine in Parkinson’s patients creates an imbalance in favor of acetylcholine, which must be compensated for with medication. Dopaminergic neurons require a lot of energy, which is mainly provided by the mitochondria (power plants of the cells). The protein pakin is present in altered form in some PD patients and becomes a trigger of the disease. Pakin is required to degrade defective mitochondria and under moderate stress this protects functional mitochondria from further damage by stimulating a survival signal. A similar function is attributed to the receptor Ret/GDNF. Both stimulate mitochondria and apparently can substitute for each other.

Etiology (Causes)

Biographic causes

  • Genetic burden – familial inherited mutations as well as inherent gene variants.
    • Genetic risk dependent on gene polymorphisms:
      • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
        • Genes: LRRK2, PARK2, PINK1, SNCA.
        • SNP: rs1790024 in the PARK2 gene
        • SNP: rs10945791 in the PARK2 gene.
        • SNP: rs34637584 in the LRRK2 gene.
          • Allele constellation: AG (15-30% risk of PD).
          • Allele constellation: AA (15-30% risk of PD).
        • SNP: rs34778348 in the LRRK2 gene.
          • Allele constellation: AG (3.0-fold).
          • Allele constellation: AA (> 3.0-fold)
        • SNP: rs33939927 in the LRRK2 gene.
          • Allele constellations: AC, CG, CT (cause Parkinson disease-8 (PARK8), rare familial form of PD).
          • Allele constellations: AA, GG, TT (cause Parkinson disease-8 (PARK8), rare familial form of PD).
        • SNP: rs35801418 in the LRRK2 gene.
          • Allele constellation: AG (causes Parkinson disease-8 (PARK8), rare familial form of PD).
          • Allele constellation: GG (causes Parkinson disease-8 (PARK8), rare familial form of Parkinson’s disease).
        • SNP: rs45478900 in the gene PINK1.
          • Allele constellation: AA (3-fold).
          • Allele constellation: AG (3-fold)
        • SNP: rs356219 in the gene SNCA
          • Allele constellation: AG (1.3-fold).
          • Allele constellation: GG (1.6-fold)
    • Genetic disorders associated with Parkinson’s disease symptomatology:
      • Ceroid lipofuscinosis
      • Gerstmann-Strausler-Scheinker disease
      • Hallervorden-Spatz disease
      • Huntington’s disease
      • Familial olivopontocerebellar atrophy
      • Wilson’s disease (copper storage disease) – autosomal recessive inherited disorder in which one or more gene mutations disrupt copper metabolism in the liver.
    • Morning type (people who like to get up early in the morning): gene variants were identified that were associated with this chronotype: 27% increased risk for morning types.
  • Age – increasing age

Behavioral causes

  • Nutrition
    • High intake of saturated fatty acids
    • Micronutrient deficiency (vital substances) – see Prevention with micronutrients.
  • Drug use
  • Physical activity
    • Physical inactivity – subjects who spent ≥ 6 hours per week being physically active in the home and commuting to work had a 43% lower risk of developing PD than subjects who spent <2 hours per week on these activities
  • Trauma-related – boxer’s encephalopathy.

Disease-related causes

  • Dementia syndromes
  • Infectious-related, e.g.
    • Postencephalitic, in Creutzfeld-Jakob disease.
    • Chronic hepatitis B (1.76-fold).
    • Chronic hepatitis C (1.29-fold) (1.51-fold)
  • Cortical-basal ganglionic degeneration.
  • Metabolic causes – e.g., due to hypoparathyroidism, hepatolenticular degeneration.
  • Alzheimer’s disease
  • Multiple system atrophy
  • REM sleep behavior disorder (RBD): characterized by vivid dreams and physical activity during dream sleep (REM sleep phase; “rapid eye movements, REM”); belongs to the group of parasomnias (sleep disorders with disturbing accompanying symptoms); 80% of all affected persons develop so-called alpha-synucleinopathy in the next 15 years; 90% are male, 80% are over 60 years old
  • Shy-Drager Syndrome
  • Truncal ganglion infarction or hemorrhage
  • Sporadic olivopontocerebellar atrophy
  • Striatonigral degeneration
  • Cerebral space neoplasm – e.g., brain tumor.
  • Cerebrovascular risk factors (vessels concerning the blood supply to the brain) that are similarly associated with the development of PD as with Alzheimer’s disease
    • Apoplexy (stroke)
    • Heart failure (cardiac insufficiency) (HR: 1.43 with PD).
    • Alzheimer’s disease (see above).
    • Obstructive sleep apnea (OSA) – pauses in breathing during sleep caused by obstruction of the airway, often occurring several hundred times per night (HR: 1.65 with PD)

Medication

Environmental pollution – intoxications (poisonings).

  • Aluminum
  • Lead
  • Cobalt
  • Disulfiram (drug that can be used to support abstinence in alcohol dependence).
  • Insecticides
    • Rotenone (pyranofurochromone derivative whose basic structure is derived from isoflavones).
  • Carbon disulfide
  • Air pollutants
    • Particulate matter (PM2.5) – 13% increased risk of disease per 5 µg/m3 increase in particulate matter at residence (hazard ratio 1.13; 1.12 to 1.14); association was dose-dependent up to a PM2.5 concentration of 16 µg/m3.
    • Carbon monoxide
  • Manganese (manganese-containing fumes during welding) → development and progression of manganese parkinsonism.
  • Methyl alcohol (methanol)
  • MPTP (1-methyl-1-4-phenyl-1,2,3,6-tetrahydropyridine) [neurotoxin].
  • Pesticides
    • Organo-chlorine pesticides – e.g. beta-hexachlorocyclohexanes (beta-HCH) were more frequently detected in patients with PD (76%) compared to a control group (40%)
  • Mercury amalgam (+58%).
  • Cyanide