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

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.

Keywords: Ageing; Mitochondria; Neurodegeneration; Parkinson's disease.

Graphical abstract

Fig. 1

Changes within SN neurons with advancing age. (A) There is an increase in the number of cells showing mitochondrial dysfunction, including a loss of key mitochondrial proteins including complex I subunits (arrow). Changes in mitochondrial membrane potential and network dyanmics have also been shown to be important for neuronal survival image B, shows the mitochondrial network of a healthy neuron within culture, fragmentation of this network is associated with changes in mitochondrial membrane potential and prior to degradation through mitophagy. There is a loss of SN neurons with advancing age, images C and D show the SN of a 69 year old and a 53 year old respectively. The loss of neurons can be seen as a loss of pigmented cells even at a low magnification in the SN of the 69 year old.

Fig. 2

Mitochondrial dysfunction has been implicated to be important for the pathogenesis of Parkinson's disease for nearly 30 years. A number of different aspects of mitochondrial biology have been linked to PD. This figure shows how a healthy mitochondrion (green) changes with advancing age, for example accumulating mitochondrial DNA deletions (shown as smaller mtDNA molecules), and becomes dysfunctional (red) and highlights key proteins and processes that have been implicated in the pathogenesis of PD. Mitochondrial DNA deletions lead to mitochondrial dysfunction and respiratory deficiencies and have been linked to the generation of ROS (yellow) and the associated oxidative stress. Changes in the expression and activity of mitochondrial electron transport chain complexes I and IV have been found in the elderly and patients with PD and inhibition of complex I causes PD like symptoms in model systems treated with toxins such as MPTP (blue/green) and rotenone (purple). The association of the mitochondria with ER has been shown to be important for mitochondrial calcium handling (green) and this association relies on mitofusin 2 and DJ-1. The buffering of calcium by the mitochondria is important for the maintenance of cellular homeostasis. Alpha-synuclein, which forms Lewy bodies, has also been shown to interact with mitochondria and affect their function. Finally proteins encoded by a number of genes known to be mutated in autosomal recessive forms of PD have functions important for mitochondrial function as well as the targeting of mitochondria to mitophagy. Once phosphorylated by Pink1 (indicated by ‘P’), Parkin ubiquinates a number of mitochondrial proteins to target the mitochondria for degradation. These processes will all affect the survival of neurons in the SN with advancing age.

Fig. 3

The degradation of proteins and organelles through the proteasome and autophagy pathways is tightly regulated and heavily ATP dependant. Both these processes have been implicated to be affected/dysregulated in Parkinson's disease. This figure reviews how these pathways are affected and the mechanism for their dysfunction. The interconnectivity between the two protein degradation pathways means that a decrease in the efficiency of one will strongly impact on the burden of the other. HSC70 – heat shock 70 kDa protein, DUB – deubiquitinating enzyme.

Fig. 4

Age related changes in a number of processes pushes substantia nigra neurons towards cell death. These changes include accumulation of mitochondrial DNA defects, oxidative damage (through a number of processes) and accumulation of neuromelanin. This increases the vulnerability of the SN neurons so that a further insult from either toxic alpha-synuclein or mitochondrial dysfunction leads to cell death. It is the accumulation of all these processes that will lead to the loss of neurons within this brain region. Several of these processes have been shown to be sufficient to cause substantia nigra neuronal loss alone and so are likely to contribute to the death of these neurons in Parkinson's disease.