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.
Highlights
Traumatic brain injury (TBI) has been implicated as a risk factor for several neurodegenerative diseases, including Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Parkinson’s Disease (PD) [148]
While the influence of sex on PD remains under investigation, less is known about the mechanistic contributions of TBI that could lead to eventual PD pathology
While TBI has been implicated in several neurodegenerative disorders the strongest emerging evidence is for a causative relationship with late onset PD
Summary
TBI has been implicated as a risk factor for several neurodegenerative diseases, including Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS), and PD [148]. Using a CCI model, Sauerbeck et al (2012) showed that exposure to either TCE or CCI alone does not result in dopaminergic neuron loss in the SNpc, but exposure to both causes 13-17% loss, suggesting a synergistic relationship between TBI and TCE exposure [131] They show mitochondrial dysfunction in the striatum without the loss of dopaminergic innervation from the SNpc. They show mitochondrial dysfunction in the striatum without the loss of dopaminergic innervation from the SNpc These three studies indicate a strong relationship between TBI and PD, key mechanistic questions remain unanswered, such as the relationship between TBI and trans-synaptic spread of more authentic α-syn Lewy body-like pathology consisting of dense perinuclear aggregates or corkscrew Lewy neurite-like structures as seen in human idiopathic PD [143]. What remains to be seen is if TBI increases expression of Rabs thereby providing abnormal substrates for LRRK2 in neurons and glial cells which may cause TBI induced PD
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