Elsevier

Toxicology in Vitro

Volume 43, September 2017, Pages 104-112
Toxicology in Vitro

Review
Neurodegenerative signaling factors and mechanisms in Parkinson's pathology

https://doi.org/10.1016/j.tiv.2017.06.008Get rights and content

Highlights

  • Parkinson's disease is second most common neurodegenerative disease.

  • Review is dealing with the degenerative factors and mechanisms of neuronal death.

  • Protein aggregation may be the primary event in neuronal death initiation.

  • Nanoparticle based drug delivery to Parkinson's patients

Abstract

Parkinson's disease (PD) is a chronic and progressive degenerative disorder of central nervous system which is mainly characterized by selective loss of dopaminergic neurons in the nigrostrial pathway. Clinical symptoms of this devastating disease comprise motor impairments such as resting tremor, bradykinesia, postural instability and rigidity. Current medications only provide symptomatic relief but fail to halt the dopaminergic neuronal death. While the etiology of dopaminergic neuronal death is not fully understood, combination of various molecular mechanisms seems to play a critical role. Studies from experimental animal models have provided crucial insights into the molecular mechanisms in disease pathogenesis and recognized possible targets for therapeutic interventions. Recent findings implicate the involvement of abnormal protein accumulation and phosphorylation, mitochondrial dysfunction, oxidative damage and deregulated kinase signaling as key molecular mechanisms affecting the normal function as well survival of dopaminergic neurons. Here we discuss the relevant findings on the PD pathology related mechanisms and recognition of the cell survival mechanisms which could be used as targets for neuroprotective strategies in preventing this devastating disorder.

Graphical abstract

Mechanism involved in PD pathology. Pictorial presentation showing the involvement of different neurodegenerative mechanisms like oxidative stress, genetic mutations, endoplasmic reticulum (ER) stress, mitochondrial dysfunction and apoptosis in dopaminergic neurons after exposure to environmental factors/neurotoxins.

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Section snippets

Parkinson's disease: overview

PD is a devastating degenerative neurological illness without cure. It includes clinical characteristics like tremor, rigidity, postural instability, bradykinesia and akinesia. Tremor is the most common and well-known symptom of PD. Although around 30% of the PD patients do not have tremor at disease onset, but the disease progression involves their development. Rigidity is an excessive and continuous contraction of the muscles which produces stiffness as well as resistance to joints movement,

Protein aggregation

Protein aggregation is a biological phenomenon which involves intracellular or extracellular accumulation of misfolded proteins (Maiti et al., 2014). Such protein aggregates are the pathological hallmark of PD pathology involving accumulation of α-synuclein (α-syn) protein in the form of Lewy bodies. Mutations in specific genes like parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2), DJ-1, alpha-synuclein, PTEN-induced putative kinase 1 (PINK1) and P-type ATPase gene-ATP13A2 have also been

Antioxidant supply

Reactive oxygen species produced under physiological conditions are in very low levels and easily neutralized by endogenous antioxidant defense system which includes the antioxidant enzymes such as glutathione reductase (GRd), glutathione peroxidise (GPx), superoxide dismutase (SOD), catalase and the antioxidant reduced glutathione (GSH). GSH is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell (Meister, 1988). Reduction in the levels of

Promising brain drug delivery to Parkinson disease

Recently, there has been an increasing interest in the development of new drug delivery systems for PD therapeutics. Available therapy like L-Dopa is targets the motor symptoms but it neither treat the neurodegenerative process nor provide neuroprotection to the surviving dopaminergic neurons (Deierborg et al., 2008). Thus, current research efforts are focused on halting neurodegeneration using promising alternatives such as antioxidants, anti-apoptotic agents, cell-based therapies and

Conclusion

PD is a complicated multifaceted disease with many causative factors involved in its pathogenesis. To date numbers of signaling pathways have been suggested in disease pathology but still it remains elusive prompting us to investigate further. The studies in last more than two decades have removed the broader outlines of disease etiology and it appears that only the fine lines remain to be removed. Brain is the most mysterious organ in human body and nothing can be said before investigation.

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