Advancing age and risk for Parkinson’s disease

I read an interesting review article recently, by Dr Reeve and colleagues in Ageing Research Reviews (14(2014) 19-30) that focused on the age-related changes to neurones in the brain that cause motor symptoms in Parkinson’s disease (PD).

 

The authors state that aging is important for the development of PD, which makes sense since 1% of adults 60+years are affected by PD, and this number increases to 5% in persons 85+years. Also, about 5% of all PD cases impact people younger than 60 years; the majority of these are thought to be linked to mutations in genes that affect protein metabolism and mitochondrial function, including the genes:

  • pink 1 (park6)
  • parkin (park 2)
  • dj-1 (park 7)
  • alpha-synuclein (park 1)

Brain region

The main cause of motor symptoms in PD result from changes to the substantia nigra (SN), specifically the “pars compacta” area where dopamine resides. Interestingly, with “regular/normal” aging, the pars compacta shows more pathological changes than any other brain region. This seems to suggest dopaminergic neurone are preferentially vulnerable to loss with any kind of aging.

Mitochondria

Mitochondria produce the cell’s energy source, ATP.

(see more on the mitochondria and it’s implications to new PD meds HERE)

With aging, and in PD, SN neurons may be predisposed to sensitivity to mitochondrial dysfunction and changes to protein degradation. This means: if the mitochondria isn’t working (maybe because of bad mitochondrial mutations), there is no energy supplied to the cells (a decreased in ATP levels within the neurons). No ATP increased calcium overload in the neurons, which cause a loss of mitochondrial bioenergetic function, and cells cannot do what they are mean to do!

With “normal” aging, we see an increased mutation leading to mitochondrialDNA (mtDNA) deletions… these is found to be most common in the SN (you guessed it!). And this is related to the amount of cell loss in the SN. This tells us disruptions in mtDNA within dopamine neurons can cause neuropathology (disease of nervous system tissues/brain) and symptoms associated with PD. It also shows the importance of mitochondrial dysfunction associated with advancing age to the probable pathogenesis (mechanisms that cause disease) of PD.

Ageing and Parkinson's disease: why is advancing age the biggest risk factor? Fig. 4.

Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Fig. 4.

Alpha Synuclein

The pathological hallmark of PD, and dementia with Lewy Bodies, is the “Lewy Body“. Lewy bodies are accumulations of protein, mostly alpha-synuclein protein. Alpha-synuclein is thought to be used for “recycling” cells/vesicles. However, lewy bodies are also seen in older adults with no signs/symptoms of PD!

All of this tells us that advancing age causes a number of processes essential for function of SN and dopamine metabolism to decline. This cell loss, however, may need to reach a certain level before the symptoms of PD develop. So, some people may only experience minor changes, and this may explain why not all individuals who age are affected by PD.

much love.

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