Ageing and Parkinson's disease: Why is advancing age the biggest risk factor? ^☆

Graphical abstract

Highlights

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  Review of age related processes occurring within substantia nigra neurons.

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  Discussion of why these neurons seem to be susceptible to loss with age.

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  Review of why SN neurons are particularly sensitive to mitochondrial dysfunction.

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  Review of why SN neurons are sensitive to changes in protein degradation pathways.

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  Discussion of relevance to Parkinson's disease pathology.

Abstract

As the second most common age related neurodegenerative disease after Alzheimer's disease, the health, social and economic impact resulting from Parkinson's disease will continue to increase alongside the longevity of the population. Ageing remains the biggest risk factor for developing idiopathic Parkinson's disease. Although research into the mechanisms leading to cell death in Parkinson's disease has shed light on many aspects of the pathogenesis of this disorder, we still cannot answer the fundamental question, what specific age related factors predispose some individuals to develop this common neurodegenerative disease. In this review we focus specifically on the neuronal population associated with the motor symptoms of Parkinson's disease, the dopaminergic neurons of the substantia nigra, and try to understand how ageing puts these neurons at risk to the extent that a slight change in protein metabolism or mitochondrial function can push the cells over the edge leading to catastrophic cell death and many of the symptoms seen in Parkinson's disease. We review the evidence that ageing is important for the development of Parkinson's disease and how age related decline leads to the loss of neurons within this disease, before describing exactly how advancing age may lead to substantia nigra neuronal loss and Parkinson's disease in some individuals.