Parkinson’s disease (PD) is a progressive neurodegenerativedisorder which leads to impaired motor skills.
The majorpathological feature of PD is the degeneration of dopaminergic (DA) neuronswhich projects from substantia nigra (SN) to thestriatum in the mid brain (nigro-striatal pathway) (1). Another neuropathological feature of PD isthe cytoplasmic inclusion of misfolded ?-synuclein protein indegenerating dopaminergic neurons called as Lewy bodies (2). The primary motor symptoms of PD, such astremor, rigidity and bradykinesia are caused by inadequate formation and neurotransmissionof dopamine within the nigro-striatal pathway (3,4). This pathway isimportant for allowing us to make voluntary movements. Patients with PD alsoshow non-motor-related symptoms such as olfactory deficits, depression,cognitive deficits and sleep disorders (5). The diseasemechanism that ultimately causes PD is largely unknown. For most cases, wedon’t know what triggered the disease, called as idiopathic or sporadic PD.
In the vast majority of cases, there isno family history of the disease. However, about 10-15% patients do have afamily history and those patients are referred to as having the familial form of PD. For these patients,their PD appears to be caused by a mutation in one of a few different genes (suchas SNCA, Parkin, LRRK2, DJ-1 etc.) (6,7). Although thedisease cause remains elusive, there are some risk factors associated withdeveloping the disease.
These risk factors are: exposure to environmentaltoxins and inherited genetic mutations. These genetic and non-genetic riskfactors have the potential to initiate neurodegeneration and subsequent chronicinflammation in the brain eventually contributing to the pathophysiology of PD (8).Innate immune response in PDTheinflammatory response takes a toll on the human body and becomes the prevalentmechanism in age-associated diseases (9). Manyneurodegenerative diseases including PD, Alzheimer’s disease (AD), amyotrophiclateral sclerosis (ALS) and multiple sclerosis (MS) have been linked withinflammation (10).
The presenceof activated glial cells, increased inflammatory molecules such as cytokines/chemokines,and increased oxidative stress and reactive oxygen species are the mainneuroinflammatory characteristics present in neurodegenerative disordersincluding PD (11). PDis now not only characterized as loss of DA-neurons and motor impairment butalso, recognized to have an inflammatory component which play crucial role inthe progression of the disease. Several inflammatory mediators such as, TNF-?,IL-1?,reactive oxygen species and nitric oxide, released from non-neuronal cellsexacerbate the disease pathology (2,12). It has beensuggested that ?-synuclein released from dying neuronsalso activate the microglia via TLR2 activation (13). Furthermore,the elevated levels of inflammatory cytokines such as TNF-?,IL-1?and IL-6 have been reported in serum, cerebrospinal fluid (CSF) and striatum ofPD patients (14).
Additionally,activation and increased number of glial cells and infiltrating peripherallymphocyte such as cytotoxic CD4+ and CD8+ cells in SN also supports the roleof adaptive immunity in the etiology of the disease (7). Overall, these studiesand others suggest the contribution of the immune system in PD pathology.Microglial activation andNeuroinflammation in PD:Microglia originatefrom erythromyeloid progenitors in the yolk sac then, during development, theymigrate away to form the central nervous system (CNS). Fully differentiatedmicroglial cells are also called resident macrophages of the CNS (15).
Growing evidencesuggests that the activation of microglia in CNS, play an important role in thepathogenesis of PD. The resting microglia switches to an activated microgliaphenotype in response to pathogen invasion or release of toxic or inflammatorymediators and thereby promotes an inflammatory response (10).