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.

3,6’-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation

“…An increasing number of epidemiological studies have implicated TBI as a major non-genetic risk factor for later development of neurodegenerative disease ( Delic et al, 2020 ), with the strongest evidence associated with PD ( Crane et al, 2016 ; Gardner et al, 2018 ). In the light of studies demonstrating the aberrant overexpression of α-synuclein coincident with neuroinflammation in brain following TBI, and suggesting α-synuclein as key a pathological link between TBI and later development of PD-like symptoms in humans and animal models of TBI ( Acosta et al, 2015 ; Wong and Hazrati, 2013 ), we evaluated whether DP and Pom could mitigate α-synuclein-induced toxicity in primary neuronal cultures containing dopaminergic neurons.…”

“…Beyond the short-term consequences of neuronal dysfunction and loss induced by TBI, biochemical cascades are initiated that can lead to an increased risk of neurodegenerative disorders and, in particular, PD ( Delic et al, 2020 ; Gardner et al, 2018 ; Crane et al, 2016 ). α-Synuclein has been proposed as the key pathological link between the chronic effects of TBI and later development of PD ( Acosta et al, 2015 ).…”

Quinpirole-Mediated Regulation of Dopamine D2 Receptors Inhibits Glial Cell-Induced Neuroinflammation in Cortex and Striatum after Brain Injury

“…Traumatic brain injury (TBI) is a global risk factor and the leading cause of neurological disability. Recent studies have reported that TBI is associated with several neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease [ 1 , 2 , 3 ]. TBI leads to a primary injury, which is followed by a secondary brain injury.…”

Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease

“…Insomnia-associated cognitive decline is associated iron accumulation, oxidative stress, and inflammation [ 73 ], and may likewise be ameliorated with IN DFO treatment. Furthermore, accumulation of iron is thought to be one of the many pathophysiological sequelae of traumatic brain injury (TBI) [ 125 ]. DFO has been shown to suppress this post-TBI iron overload as well as reverse hydrocephalus and cognitive deficits following TBI in animal models [ 79 , 126 , 127 , 128 ].…”

“…DFO has been shown to suppress this post-TBI iron overload as well as reverse hydrocephalus and cognitive deficits following TBI in animal models [ 79 , 126 , 127 , 128 ]. The sequelae of TBI combine neurodegenerative, neuroinflammatory, and both ischemic and hemorrhagic neurovascular components [ 125 ], a perfect model wherein DFO may uniquely enact beneficial impact through its multiple intersecting disease-modifying mechanisms.…”