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

Parkinson’sdisease: a chronic neurodegenerative and neuroinflammatory diseaseParkinson’sdisease (PD) is a progressive neurodegenerative disorder which leads toimpaired motor skills. Themajor pathological feature of PD is degeneration of dopaminergic (DA) neuronswhich projects from substantia nigra (SN) to thestriatum in the mid brain (nigro-striatal pathway). Otherneuropathological features of PD are the cytoplasmic inclusion of misfolded ?-synuclein protein indegenerating dopaminergic neurons called as Lewy bodies and the reactivegliosis.

The primary motor symptoms ofPD, such as tremor, rigidity and bradykinesia are caused by inadequateformation and neurotransmission of dopamine within the nigro-striatal pathwaywhich is important for allowing us to make voluntary movements. Patients withPD also show non-motor-related symptoms such as olfactory deficits, depression,cognitive deficits and sleep disorders (19680598).The diseasemechanism that ultimately causes PD is largely unknown, for majority of caseswe actually don’t know what triggered the disease, called as idiopathic or sporadic PD. While in vastmajority 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.

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For these patientstheir 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 remainselusive but there are some risk factors associated with developing the diseasesuch as exposure to environmental toxins including inherited genetic mutationswhich have potential to initiate neurodegeneration and subsequent chronic inflammationin the brain eventually contributing to the pathophysiology of PD.Innate immune response in PDImmune system isknown to regulate the series of events including production of cytokines,resistance to inflammatory or toxic stimuli and regeneration or repair oftissues via complex intracellular signaling pathways. The inflammatory responsetakes a toll on the human body and becomes the prevalent mechanism inage-associated diseases. Many neurodegenerative diseases including Alzheimer’sdisease (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 ascytokines and chemokines, and increased oxidative stress and reactive oxygenspecies are the main neuroinflammatory characteristics present in neurodegenerativedisorders including PD (29153601). Now, PD is not onlycharacterized as loss of DA-neurons and motor impairment but also recognized tohave an inflammatory component which play crucial role in the progression ofthe disease. Several inflammatory mediators such as TNF-?, IL-1?, reactive oxygen species andnitric oxide released from non-neuronal cells also exacerbate the diseasepathology (23318001).

It has been suggested that a-syn released from dyingneurons 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 inserum, cerebrospinal fluid (CSF) and striatum of PD patients (19296921).Additionally, activation and increased number of glial cells and infiltratingperipheral lymphocyte such as cytotoxic CD4+ and CD8+ cells in SN also supportsthe role of adaptive immunity in the etiology of the disease (22315722).Microglial activation and Neuroinflammation in PD:Growing evidencesuggests that the activation of microglia in central nervous system, playimportant role in pathogenesis of PD. The resting microglia switches to anactivated microglia in response to pathogen invasion or release of toxic orinflammatory mediators and thereby promotes an inflammatory response.

Onceactivated, microglial cells produce a wide range of inflammatory mediatorswhich serve to initiate an innate immune response or glial cell-propagatedinflammation termed as neuroinflammation. Also, the degenerating DA-neuronsrelease many toxic factors that activate microglia and these degeneratingneurons are vulnerable to inflammatory insult and co-localize or attract alarge population of microglia in SN. Collectively, these activated microgliaand damaged neurons form a vicious cycle that leads to chronic inflammation andextensive DA neurodegeneration over a long period of time leading to the knownetiology for the progression of PD (17180163).

However, it is notwell defined whether microglia activation is beneficial or detrimental toneuronal survival, and how microglial activity is regulated.  It is, however, well-accepted that microglialactivation is required for neuronal survival, but that over-activated microglialcells are detrimental and neurotoxic. These findings confirm neuro-inflammationas a pivotal process in the progression of neurodegenerative disorders includingPD and targeting neuro-inflammatory pathways could be a tremendous step in thedevelopment of new therapeutics for all neurodegenerative diseases includingPD.Parkinson’sdisease: a chronic neurodegenerative and neuroinflammatory diseaseParkinson’sdisease (PD) is a progressive neurodegenerative disorder which leads toimpaired motor skills.

Themajor pathological feature of PD is degeneration of dopaminergic (DA) neuronswhich projects from substantia nigra (SN) to thestriatum in the mid brain (nigro-striatal pathway). Otherneuropathological features of PD are the cytoplasmic inclusion of misfolded ?-synuclein protein indegenerating dopaminergic neurons called as Lewy bodies and the reactivegliosis. The primary motor symptoms ofPD, such as tremor, rigidity and bradykinesia are caused by inadequateformation and neurotransmission of dopamine within the nigro-striatal pathwaywhich is important for allowing us to make voluntary movements.

Patients withPD also show non-motor-related symptoms such as olfactory deficits, depression,cognitive deficits and sleep disorders (19680598).The diseasemechanism that ultimately causes PD is largely unknown, for majority of caseswe actually don’t know what triggered the disease, called as idiopathic or sporadic PD. While in vastmajority 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 patientstheir 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 remainselusive but there are some risk factors associated with developing the diseasesuch as exposure to environmental toxins including inherited genetic mutationswhich have potential to initiate neurodegeneration and subsequent chronic inflammationin the brain eventually contributing to the pathophysiology of PD.Innate immune response in PDImmune system isknown to regulate the series of events including production of cytokines,resistance to inflammatory or toxic stimuli and regeneration or repair oftissues via complex intracellular signaling pathways. The inflammatory responsetakes a toll on the human body and becomes the prevalent mechanism inage-associated diseases. Many neurodegenerative diseases including Alzheimer’sdisease (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 ascytokines and chemokines, and increased oxidative stress and reactive oxygenspecies are the main neuroinflammatory characteristics present in neurodegenerativedisorders including PD (29153601). Now, PD is not onlycharacterized as loss of DA-neurons and motor impairment but also recognized tohave an inflammatory component which play crucial role in the progression ofthe disease. Several inflammatory mediators such as TNF-?, IL-1?, reactive oxygen species andnitric oxide released from non-neuronal cells also exacerbate the diseasepathology (23318001). It has been suggested that a-syn released from dyingneurons 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 inserum, cerebrospinal fluid (CSF) and striatum of PD patients (19296921).Additionally, activation and increased number of glial cells and infiltratingperipheral lymphocyte such as cytotoxic CD4+ and CD8+ cells in SN also supportsthe role of adaptive immunity in the etiology of the disease (22315722).

Microglial activation and Neuroinflammation in PD:Growing evidencesuggests that the activation of microglia in central nervous system, playimportant role in pathogenesis of PD. The resting microglia switches to anactivated microglia in response to pathogen invasion or release of toxic orinflammatory mediators and thereby promotes an inflammatory response. Onceactivated, microglial cells produce a wide range of inflammatory mediatorswhich serve to initiate an innate immune response or glial cell-propagatedinflammation termed as neuroinflammation. Also, the degenerating DA-neuronsrelease many toxic factors that activate microglia and these degeneratingneurons are vulnerable to inflammatory insult and co-localize or attract alarge population of microglia in SN. Collectively, these activated microgliaand damaged neurons form a vicious cycle that leads to chronic inflammation andextensive DA neurodegeneration over a long period of time leading to the knownetiology for the progression of PD (17180163).However, it is notwell defined whether microglia activation is beneficial or detrimental toneuronal survival, and how microglial activity is regulated.  It is, however, well-accepted that microglialactivation is required for neuronal survival, but that over-activated microglialcells are detrimental and neurotoxic. These findings confirm neuro-inflammationas a pivotal process in the progression of neurodegenerative disorders includingPD and targeting neuro-inflammatory pathways could be a tremendous step in thedevelopment of new therapeutics for all neurodegenerative diseases includingPD.