Biological links between traumatic brain injury and Parkinson's disease

Abstract

Parkinson's Disease (PD) is a progressive neurodegenerative disorder with no cure. Clinical presentation is characterized by postural instability, resting tremors, and gait problems that result from progressive loss of A9 dopaminergic neurons in the substantia nigra pars compacta. Traumatic brain injury (TBI) has been implicated as a risk factor for several neurodegenerative diseases, but the strongest evidence is linked to development of PD. Mild TBI (mTBI), is the most common and is defined by minimal, if any, loss of consciousness and the absence of significant observable damage to the brain tissue. mTBI is responsible for a 56% higher risk of developing PD in U.S. Veterans and the risk increases with severity of injury. While the mounting evidence from human studies suggests a link between TBI and PD, fundamental questions as to whether TBI nucleates PD pathology or accelerates PD pathology in vulnerable populations remains unanswered. Several promising lines of research point to inflammation, metabolic dysregulation, and protein accumulation as potential mechanisms through which TBI can initiate or accelerate PD. Amyloid precursor protein (APP), alpha synuclein (α-syn), hyper-phosphorylated Tau, and TAR DNA-binding protein 43 (TDP-43), are some of the most frequently reported proteins upregulated following a TBI and are also closely linked to PD. Recently, upregulation of Leucine Rich Repeat Kinase 2 (LRRK2), has been found in the brain of mice following a TBI. Subset of Rab proteins were identified as biological substrates of LRRK2, a protein also extensively linked to late onset PD. Inhibition of LRRK2 was found to be neuroprotective in PD and TBI models. The goal of this review is to survey current literature concerning the mechanistic overlap between TBI and PD with a particular focus on inflammation, metabolic dysregulation, and aforementioned proteins. This review will also cover the application of rodent TBI models to further our understanding of the relationship between TBI and PD.

Figure 1

Potential influences of TBI on the course of PD. In the healthy brain the blood brain barrier (BBB) is intact, microglia are highly ramified and astrocytes are non-reactive and provide nourishment to neurons (a). In prodromal PD, degenerating neurons develop alpha synuclein pathology in the form of Lewy bodies and Lewy neurites, microglia become more amoeboid and phagocytic, BBB is compromised and peripheral immune cells infiltrate the brain where they become activated and take on a role similar to that of phagocytic resident microglia (b). After a TBI, BBB is temporarily permeabilized allowing infiltration of the peripheral immune cells, astrocytes become reactive and some neurons degenerate (c). In the clinical PD, the substantia nigra pars compacta is almost entirely devoid of dopaminergic neurons, and surviving neurons in nigra and other affected brain areas are burdened with alpha synuclein pathology while the areas vacated by dying neurons are filled with reactive astrocytes, microglia, and peripheral immune cells (d). Overlap in pathology induced by TBI and present in prodromal PD may allow for TBI to accelerate prodromal PD to clinical PD.