Sunday, June 16, 2013

Mitochondrial Dysfunction and Parkinson's Disease

If you would like basic some information on mitochondria, oxidative phosphorylation, etc, take a look at mitochondrial dysfunction 

Parkinson’s Disease 

Parkinson’s disease (PD) is a neurodegenerative disease that results from the death of dopamine producing (dopaminergic) neurons in the substantia nigra (SN).  Like many neurotransmitters, dopamine has many effects on brain function such as motivation, reward and controlling movement.  Symptoms of Parkinson’s disease include tremors, difficulty walking and later on, cognitive impairment.  PD can be caused by a few rare gene mutations, but is generally considered to have no known cause. 

The standard treatment for PD is L-DOPA (the precursor of dopamine) because dopamine can’t cross the blood brain barrier, but L-DOPA can.  But the dopaminergic neurons need to convert L-DOPA to dopamine and become less able to make the conversion as the disease progresses 

* PD symptoms appear when about 60-80% of the dopaminergic neurons in the SN die 

Mitochondrial Dysfunction in Parkinson’s Disease 

Mitochondrial dysfunction has been seen in people with PD and animal models of PD:

  • People with PD have defects and lower activity in complex 1 of the electron transport chain.  Complex 1 defects increase the generation of free radicals and reduce ATP production [1]
  • People with PD have higher lactate levels (suggests a poor aerobic metabolism) [2]
  • People with PD have lower levels of CoQ10 in their serum and platelets [3]
  • Glutathione depletion precedes neuron death in the substantia nigra [1] [4]

Mitochondrial genetics are associated with PD.  Mutations in mtDNA or DNA related to mitochondrial function (such as PINK1 of the PINK1/LTEN/AMPK pathway and parkin) can cause PD and can account for some of the heritability (which is only 15%).  PINK1 and parkin cooperate to maintain mitochondrial homeostasis and overexpressing PINK1 is neuroprotective [1].  For some PD related genes see this table 

In addition, a toxin called MTPT (a synthetic opiate) and a pesticide called rotenone (which some legumes contain by the way) impair mitochondrial function, which results in Parkinson’s like symptoms and pathology in the substantia nigra neurons [1].  MTPT and rotenone are often used as animal models of PD 

Why the Dopaminergic Neurons of the Substantia Nigra? 

The dopaminergic neurons in the SN are particularly vulnerable to oxidative stress and mitochondrial dysfunction for the following reasons:
  • They have low levels of antioxidants [5]
  • They contain a lot of dopamine, melanin and lipids that are vulnerable to oxidation [5]
  • The SN has about 4.5 times the concentration of microglia than the rest of the brain, which are kind of like macrophages in the central nervous system* [6]
  • They use a lot of energy because they are large neurons that have many synapses [4] 

* Which is probably why the dopaminergic neurons of the substantia nigra, but not other dopaminergic neurons, are more vulnerable [5] 

The Mitochondria as a Therapeutic Target for Parkinson’s Disease 

Supporting mitochondrial function can improve measures of Parkinson’s disease in animal models:

  • MPTP caused an animal model of PD model in mice (decreased dopamine levels and increased oxidised glutathione and malondialdehyde).  The combination of creatine and CoQ10 protected against most of the MPTP damage [7]
  • Rotenone caused an animal model of PD in rats (decreased neurons in substantia nigra, dopamine levels, ATP in the substantia nigra and glutathione, SOD and catalase activity, and increased lipid peroxides, protein carbonyls and immune activity).  Carnitine and alpha lipoic acid protected against most of the rotenone damage [8]
  • AMPK protects against mitochondrial dysfunction and dopamine loss in an unusual animal model of PD, flies with either a LRRK2 mutation or parkin gene KO [9] 

And in humans: supplementing coenzyme Q10 slowed down Parkinson’s disease symptoms and the benefit was greatest in those who had the highest dose (1200 mg) [3] 

Other Factors 

I don’t think mitochondrial dysfunction is the only factor in PD.  Just very briefly, some other factors in PD include: 

  • Polymorphisms in pro-inflammatory cytokines [5]
  • LPS, where a single large injection of LPS resulted in a progressive loss of dopaminergic neurons: a 23% loss at 7 months and 47% loss at 10 months [6]
  • 20% lower BDNF mRNA in the SN [10]

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