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Parkinson’s disease (PD) is a progressive neurodegenerative
disorder which leads to impaired motor skills. The major
pathological feature of PD is the degeneration of dopaminergic (DA) neurons
which projects from substantia nigra (SN) to the
striatum in the mid brain (nigro-striatal pathway) (1). Another neuropathological feature of PD is
the cytoplasmic inclusion of misfolded ?-synuclein protein in
degenerating dopaminergic neurons called as Lewy bodies (2). The primary motor symptoms of PD, such as
tremor, rigidity and bradykinesia are caused by inadequate formation and neurotransmission
of dopamine within the nigro-striatal pathway (3,4). This pathway is
important for allowing us to make voluntary movements. Patients with PD also
show non-motor-related symptoms such as olfactory deficits, depression,
cognitive deficits and sleep disorders (5). The disease
mechanism that ultimately causes PD is largely unknown. For most cases, we
don’t know what triggered the disease, called as idiopathic or sporadic PD. In the vast majority of cases, there is
no family history of the disease. However, about 10-15% patients do have a
family 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 (such
as SNCA, Parkin, LRRK2, DJ-1 etc.) (6,7). Although the
disease cause remains elusive, there are some risk factors associated with
developing the disease. These risk factors are: exposure to environmental
toxins and inherited genetic mutations. These genetic and non-genetic risk
factors have the potential to initiate neurodegeneration and subsequent chronic
inflammation in the brain eventually contributing to the pathophysiology of PD (8).

Innate immune response in PD

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inflammatory response takes a toll on the human body and becomes the prevalent
mechanism in age-associated diseases (9). Many
neurodegenerative diseases including PD, Alzheimer’s disease (AD), amyotrophic
lateral sclerosis (ALS) and multiple sclerosis (MS) have been linked with
inflammation (10). The presence
of activated glial cells, increased inflammatory molecules such as cytokines/chemokines,
and increased oxidative stress and reactive oxygen species are the main
neuroinflammatory characteristics present in neurodegenerative disorders
including PD (11).  

is now not only characterized as loss of DA-neurons and motor impairment but
also, recognized to have an inflammatory component which play crucial role in
the progression of the disease. Several inflammatory mediators such as, TNF-?,
reactive oxygen species and nitric oxide, released from non-neuronal cells
exacerbate the disease pathology (2,12). It has been
suggested that ?-synuclein released from dying neurons
also activate the microglia via TLR2 activation (13). Furthermore,
the elevated levels of inflammatory cytokines such as TNF-?,
and IL-6 have been reported in serum, cerebrospinal fluid (CSF) and striatum of
PD patients (14). Additionally,
activation and increased number of glial cells and infiltrating peripheral
lymphocyte such as cytotoxic CD4+ and CD8+ cells in SN also supports the role
of adaptive immunity in the etiology of the disease (7). Overall, these studies
and others suggest the contribution of the immune system in PD pathology.

Microglial activation and
Neuroinflammation in PD:

Microglia originate
from erythromyeloid progenitors in the yolk sac then, during development, they
migrate away to form the central nervous system (CNS). Fully differentiated
microglial cells are also called resident macrophages of the CNS (15). Growing evidence
suggests that the activation of microglia in CNS, play an important role in the
pathogenesis of PD. The resting microglia switches to an activated microglia
phenotype in response to pathogen invasion or release of toxic or inflammatory
mediators and thereby promotes an inflammatory response (10). 

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