Before dopamine depletion – a chronological model for the loss of dopamine neurons in Parkinson’s Disease

I propose a theoretical model linking oxidative stress, mitochondrial dysfunction and the degeneration of axons of dopaminergic neurons in the striatum. These axons have reduced capacity to combat mitochondrial dysfunction due their very long supply lines from the nucleus. As a result they suffer energy loss due to mitochondrial dysfunction which causes retrograde degeneration and dopamine depletion in Parkinson’s disease.

Parkinson’s disease is characterized by the loss of dopaminergic neurons in the substantia nigra (SN) in the midbrain and a deficit of dopamine in the terminal synapses in the striatum, but a simple model presenting the stages leading up to this condition has so far not been presented.

This article proposes a model that schematically represents the chronology of the major events believed to be involved in the pathogenesis of Parkinson’s disease in a way designed to be accessible to patients. The model also proposes which steps may be subject to influence through medical or patient intervention, so that patients can make informed decisions about how to manage their own condition. The model covers the progression of Parkinson’s disease from benign redox imbalance in brain cells to chronic oxidative stress which initiates a cascade of two major events: (i) mitochondrial dysfunction, a condition which reduces the energy available to host cells and (ii) degeneration of vulnerable axons in the striatum region of SN neurons as a consequence of this energy loss. The model links these major events and draws attention to the considerable delays occurring between the beginning of the events and the observation of symptoms eventually produced by them, a situation which masks the true progression of the disease.

To build this model, evidence for the three major conditions already identified in the progression of Parkinson’s disease; age-related oxidative stress, mitochondrial damage and loss of dopaminergic SN neurons was investigated. There are convincing arguments for the processes that link these conditions and make up the basic version of the model. Each process has also been examined in more detail to consider the potential roles other factors having the capacity to modify or invalidate the primary model, such as α-synuclein, genetic variants, toxins or lifestyle. These additional factors add complexity to the model but help to understand how the pathogenesis and development of Parkinson’s disease is multifactorial. This article presents the simplified model only. The more complex model will be presented at a later date.