Genetic Neuropathology of Parkinson's Disease.

ArticleinInternational journal of clinical and experimental pathology 1(3):217-31 · February 2008with20 Reads
Source: PubMed
Parkinson's disease (PD) has long been considered to be a sporadic entity, perhaps with an environmental etiology. However, recent genetic discoveries have challenged this view, as there are many families with diseases of Mendelian inheritance that clinically resemble PD. Here, we will review in detail the neuropathological data relating to familial cases of PD. We will discuss the complicated relationships between the genetically defined cases and the two key pathological events seen in PD, namely loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of protein inclusions, Lewy bodies, in the neurons that survive to the end stage of the disease course. These observations will be synthesized into an overall scheme that emphasizes the two key aspects of the neuropathology as distinct events and suggest that each gene tells us something a little different about the neuropathology of PD.
    • "Formation of eosinophilic cytoplasmic inclusions, lewy bodies (LBs) in neuronal cells, neurites, astrocytes and oligodendroglial cells in brain lead to neuronal degeneration [4]. It is well established that oxidative stress and inflammation are the two major factors in pathogenesis of PD [3][4][5] . Free radicals are involved in the development of the systemic inflammatory response via microglia, T and B cells that leads to over production of neurotoxic inflammatory factors including TNF and (IL-1) [6,7]. "
    [Show abstract] [Hide abstract] ABSTRACT: Over production of reactive oxygen species (ROS) is postulated to be the main contributor in degeneration of nigrostriatal dopaminergic neurons. In this study we investigated the effects of WR1065, a free radical scavenger, on motor imbalance, oxidative stress parameters and inflammatory cytokines in CSF and brain of hemi-parkinsonian rats. Lesion of dopaminergic neurons was done by unilateral infusion of 6-hydroxydopamine in to the central region of the substentia nigra pars compacta (SNc) to induce hemi-parkinsonism and motor imbalance in rats. WR1065 (20, 40 and 80 μg/2 μl/rat) was administered three days before 6-OHDA administration. After three weeks behavioral study was performed and then brain and CSF samples were collected to assess tumor necrosis factor (TNFα), interlukin (IL-1β), reduced glutathione (GSH), and malondialdehyde (MDA). WR1065 pre-treatment in rats before receiving 6-OHDA, improved significantly motor impairment and caused reduction of MDA and inflammatory cytokines TNFα and IL-1β levels, while GSH level significantly increased when compared with lesioned rats. Our study indicated that WR1065 could improve 6-OHDA-induced motor imbalance. Furthermore, it decreased lipid peroxidation and inflammatory cytokines and restored the level of GSH up to normal range. We suggest that WR1065 can be proposed as a potential neuroprotective agent in motor impairments of PD. However to prove this hypothesis more clinical trial studies should be done.
    Full-text · Article · May 2016
    • "The decrease in dopamine levels in the putamen and corpus striatum followed by neuronal cell death in the SN leads to the emergence of motor symptoms described above. Clinical studies have demonstrated that motor symptoms emerge when there is death of 60–80% of dopaminergic neurons of the SNc and an 80% decrease in the level of dopamine in the putamen [121, 130, 131]. In PD, the aggregation of LBs and Lewy neurites consisting of proteins, fats and polysaccharides, with radiating filaments (including α-syn, neurofilaments, ubiquitin, parkin, and synphilin) is observed in the substantia innominata [115, 132]. "
    [Show abstract] [Hide abstract] ABSTRACT: The mevalonate cascade is a key metabolic pathway that regulates a variety of cellular functions and is thereby implicated in the pathophysiology of most brain diseases, including neurodevelopmental and neurodegenerative disorders. Emerging lines of evidence suggest that statins and Rho GTPase inhibitors are efficacious and have advantageous properties in treatment of different pathologic conditions that are relevant to the central nervous system. Beyond the original role of statins in lowering cholesterol synthesis, they have anti-inflammatory, antioxidant and modulatory effects on signaling pathways. Additionally, Rho GTPase inhibitors and statins share the mevalonate pathway as a common target of their therapeutic actions. In this review, we discuss potential mechanisms through which these drugs, via their role in the mevalonate pathway, exert their neuroprotective effects in neurodegenerative and neurodevelopmental disorders.
    Article · Jan 2016
    • "2.2.1. OCs and PD PD, being a debilitating progressive neurodegenerative disorder, is characterized by the depletion of dopaminergic neurons located in the substantia nigra pars compacta (SNc), basal nuclei, and tectum mesencephalicum, with subsequent decrease of dopamine levels in the putamen and in the corpus striatum and the emergence of motor symptoms9899100101102103104. It is the second most common age-related disease after AD with high prevalence in industrialized countries [100,105]. "
    [Show abstract] [Hide abstract] ABSTRACT: Organochlorine pesticides (OCPs) are persistent and bioaccumulative environmental contaminants with potential neurotoxic effects. The growing body of evidence has demonstrated that prenatal exposure to organochlorines (OCs) is associated with impairment of neuropsychological development. The hypothesis is consistent with recent studies emphasizing the correlation of environmental as well as genetic factors to the pathophysiology of neurodevelopmental and neurobehavioral defects. It has been suggested that maternal exposure to OCPs results in impaired motor and cognitive development in newborns and infants. Moreover, in utero exposure to these compounds contributes to the etiology of autism. Although impaired neurodevelopment occurs through prenatal exposure to OCs, breastfeeding causes postnatal toxicity in the infants. Parkinson's disease (PD) is another neurological disorder, which has been associated with exposure to OCs, leading to α-synuclein accumulation and depletion of dopaminergic neurons. The study aimed to review the potential association between pre- and post-natal exposure to OCs and impaired neurodevelopmental processes during pregnancy and neuropsychological diseases such as PD, behavioral alterations, seizures and autism.
    Full-text · Article · Nov 2015
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