Parkinson’s Parkin, LRRK2, DJ-1 etc.). Although the disease cause

Parkinson’s
disease: a chronic neurodegenerative and neuroinflammatory disease

Parkinson’s
disease (PD) is a progressive neurodegenerative disorder which leads to
impaired motor skills. The
major pathological feature of PD is degeneration of dopaminergic (DA) neurons
which projects from substantia nigra (SN) to the
striatum in the mid brain (nigro-striatal pathway). Other
neuropathological features of PD are the cytoplasmic inclusion of misfolded ?-synuclein protein in
degenerating dopaminergic neurons called as Lewy bodies and the reactive
gliosis. 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
which 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 (19680598).

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The disease
mechanism that ultimately causes PD is largely unknown, for majority of cases
we actually don’t know what triggered the disease, called as idiopathic or sporadic PD. While in vast
majority of cases, there is no family history of the disease but about 10-15%
patients do have family history and those patients referred to have 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.). Although the disease cause remains
elusive but there are some risk factors associated with developing the disease
such as exposure to environmental toxins including inherited genetic mutations
which have potential to initiate neurodegeneration and subsequent chronic inflammation
in the brain eventually contributing to the pathophysiology of PD.

Innate immune response in PD

Immune system is
known to regulate the series of events including production of cytokines,
resistance to inflammatory or toxic stimuli and regeneration or repair of
tissues via complex intracellular signaling pathways. The inflammatory response
takes a toll on the human body and becomes the prevalent mechanism in
age-associated diseases. Many neurodegenerative diseases including Alzheimer’s
disease (AD), PD, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS)
have been linked with inflammation. The presence of activated glial cells,
participation of innate immune system, increased inflammatory molecules such as
cytokines and chemokines, and increased oxidative stress and reactive oxygen
species are the main neuroinflammatory characteristics present in neurodegenerative
disorders including PD (29153601).

Now, PD is 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-?, IL-1?, reactive oxygen species and
nitric oxide released from non-neuronal cells also exacerbate the disease
pathology (23318001). It has been suggested that a-syn released from dying
neurons also activate the microglia via TLR2 activation (23463005).
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 of PD patients (19296921).
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 (22315722).

Microglial activation and Neuroinflammation in PD:

Growing evidence
suggests that the activation of microglia in central nervous system, play
important role in pathogenesis of PD. The resting microglia switches to an
activated microglia in response to pathogen invasion or release of toxic or
inflammatory mediators and thereby promotes an inflammatory response. Once
activated, microglial cells produce a wide range of inflammatory mediators
which serve to initiate an innate immune response or glial cell-propagated
inflammation termed as neuroinflammation. Also, the degenerating DA-neurons
release many toxic factors that activate microglia and these degenerating
neurons are vulnerable to inflammatory insult and co-localize or attract a
large population of microglia in SN. Collectively, these activated microglia
and damaged neurons form a vicious cycle that leads to chronic inflammation and
extensive DA neurodegeneration over a long period of time leading to the known
etiology for the progression of PD (17180163).

However, it is not
well defined whether microglia activation is beneficial or detrimental to
neuronal survival, and how microglial activity is regulated.  It is, however, well-accepted that microglial
activation is required for neuronal survival, but that over-activated microglial
cells are detrimental and neurotoxic. These findings confirm neuro-inflammation
as a pivotal process in the progression of neurodegenerative disorders including
PD and targeting neuro-inflammatory pathways could be a tremendous step in the
development of new therapeutics for all neurodegenerative diseases including
PD.Parkinson’s
disease: a chronic neurodegenerative and neuroinflammatory disease

Parkinson’s
disease (PD) is a progressive neurodegenerative disorder which leads to
impaired motor skills. The
major pathological feature of PD is degeneration of dopaminergic (DA) neurons
which projects from substantia nigra (SN) to the
striatum in the mid brain (nigro-striatal pathway). Other
neuropathological features of PD are the cytoplasmic inclusion of misfolded ?-synuclein protein in
degenerating dopaminergic neurons called as Lewy bodies and the reactive
gliosis. 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
which 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 (19680598).

The disease
mechanism that ultimately causes PD is largely unknown, for majority of cases
we actually don’t know what triggered the disease, called as idiopathic or sporadic PD. While in vast
majority of cases, there is no family history of the disease but about 10-15%
patients do have family history and those patients referred to have 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.). Although the disease cause remains
elusive but there are some risk factors associated with developing the disease
such as exposure to environmental toxins including inherited genetic mutations
which have potential to initiate neurodegeneration and subsequent chronic inflammation
in the brain eventually contributing to the pathophysiology of PD.

Innate immune response in PD

Immune system is
known to regulate the series of events including production of cytokines,
resistance to inflammatory or toxic stimuli and regeneration or repair of
tissues via complex intracellular signaling pathways. The inflammatory response
takes a toll on the human body and becomes the prevalent mechanism in
age-associated diseases. Many neurodegenerative diseases including Alzheimer’s
disease (AD), PD, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS)
have been linked with inflammation. The presence of activated glial cells,
participation of innate immune system, increased inflammatory molecules such as
cytokines and chemokines, and increased oxidative stress and reactive oxygen
species are the main neuroinflammatory characteristics present in neurodegenerative
disorders including PD (29153601).

Now, PD is 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-?, IL-1?, reactive oxygen species and
nitric oxide released from non-neuronal cells also exacerbate the disease
pathology (23318001). It has been suggested that a-syn released from dying
neurons also activate the microglia via TLR2 activation (23463005).
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 of PD patients (19296921).
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 (22315722).

Microglial activation and Neuroinflammation in PD:

Growing evidence
suggests that the activation of microglia in central nervous system, play
important role in pathogenesis of PD. The resting microglia switches to an
activated microglia in response to pathogen invasion or release of toxic or
inflammatory mediators and thereby promotes an inflammatory response. Once
activated, microglial cells produce a wide range of inflammatory mediators
which serve to initiate an innate immune response or glial cell-propagated
inflammation termed as neuroinflammation. Also, the degenerating DA-neurons
release many toxic factors that activate microglia and these degenerating
neurons are vulnerable to inflammatory insult and co-localize or attract a
large population of microglia in SN. Collectively, these activated microglia
and damaged neurons form a vicious cycle that leads to chronic inflammation and
extensive DA neurodegeneration over a long period of time leading to the known
etiology for the progression of PD (17180163).

However, it is not
well defined whether microglia activation is beneficial or detrimental to
neuronal survival, and how microglial activity is regulated.  It is, however, well-accepted that microglial
activation is required for neuronal survival, but that over-activated microglial
cells are detrimental and neurotoxic. These findings confirm neuro-inflammation
as a pivotal process in the progression of neurodegenerative disorders including
PD and targeting neuro-inflammatory pathways could be a tremendous step in the
development of new therapeutics for all neurodegenerative diseases including
PD.