Genetic Neuropathology of Parkinson's Disease.

Laboratory of Neurogenetics, National Institute on Aging, Bethesda MD, USA.
International journal of clinical and experimental pathology (Impact Factor: 1.89). 02/2008; 1(3):217-31.
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.

Full-text preview

Available from:
  • Source
    • "Resting tremor, bradykinesia, rigidity, and postural instability are the main clinical manifestations of this disease. One of the features of PD is that its basic clinical signs appear in the late stages of the development of the neurodegenerative processes in the pars compacta of the substantia nigra, when about 60% of the DA neurons of the substantia nigra have died and dopamine levels in the striatum have decreased by 80% [2] [3]. From a genetic point of view, PD is a heterogeneous pathology. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is a widespread neurodegenerative disorder. Despite the intensive studies of this pathology, in general, the picture of the etiopathogenesis has still not been clarified fully. To understand better the mechanisms underlying the pathogenesis of PD, we analyzed the expression of 10 genes in the peripheral blood of treated and untreated patients with PD. 35 untreated patients with PD and 12 treated patients with Parkinson's disease (Hoehn and Yahr scores 1-2) were studied. An analysis of the mRNA levels of ATP13A2, PARK2, PARK7, PINK1, LRRK2, SNCA, ALDH1A1, PDHB, PPARGC1A, and ZNF746 genes in the peripheral blood of patients was carried out using reverse transcription followed by real-time PCR. A statistically significant and specific increase by more than 1.5-fold in the expression of the ATP13A2, PARK7, and ZNF746 genes was observed in patients with PD. Based on these results, it can be suggested that the upregulation of the mRNA levels of ATP13A2, PARK7, and ZNF746 in untreated patients in the earliest clinical stages can also be observed in the preclinical stages of PD, and that these genes can be considered as potential biomarkers of the preclinical stage of PD.
    Full-text · Article · Oct 2015 · Parkinson's Disease
  • Source
    • "There are good reasons to distinguish between the different genes for parkinsonism. It has been argued persuasively, for example, that a-synuclein positive Lewy bodies are important for assignment of a disease to PD (Hardy and Lees 2005) but this position is complicated by the fact that not all LRRK2 cases have Lewy bodies despite being clinically homogenous (Cookson et al. 2008). Clinical information is also useful, and would suggest distinction between recessive and dominant genes, but as discussed for ATP13A2 and Fbxo7, there can be a wide range of symptoms for mutations in a single gene (Ramirez et al. 2006; G€ und€ uz et al. 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Substantial progress has been made in the genetic basis of Parkinson's disease (PD). In particular, by identifying genes that segregate with inherited PD or show robust association with sporadic disease, and by showing the same genes are found on both lists, we have generated an outline of the cause of this condition. Here, we will discuss what those genes tell us about the underlying biology of PD. We specifically discuss the relationships between protein products of PD genes and show that common links include regulation of the autophagy-lysosome system, an important way by which cells recycle proteins and organelles. We also discuss whether all PD genes should be considered to be in the same pathway and propose that in some cases the relationships are closer while in other cases the interactions are more distant and might be considered separate. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Preview · Article · Jul 2015 · Journal of Neurochemistry
  • Source
    • "For example, our lab has shown that toxic manganese exposure can induce aggregation and altered uptake of a-Syn in rat primary choroid plexus cells within 2 hours [49]. In addition, there are many genetic mutations in proteins other than a-Syn that contribute to a-Syn toxicity and PD development [52,53]. The G2019S LRRK2 mutation, the most common mutation found in familial PD phenotypes, has been showed to interact with a-Syn during chaperone-mediated autophagy and consequently, promote a-Syn dysfunction [54]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of α-Synuclein (a-Syn) into Lewy body inclusions and the loss of dopaminergic neurons in the substantia nigra (SN). Accumulation of a-Syn can induce a progressive, cyclical pathology that results in the transmission of toxic, aggregated a-Syn species to healthy neurons, leading to further neurodegeneration such as occurs in PD. The blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barriers (BCSFB) are responsible for regulating the access of nutrients and other molecules to the brain, but very little is known about their regulatory roles in maintaining the homeostasis of a-Syn in the CSF and brain parenchyma. This review analyzes the current literature reports on the transport of a-Syn by various brain cell types with a particular focus on the potential transport mechanisms of a-Syn at the BBB and BCSFB. The indication of altered a-Syn transport by brain barriers in PD pathoetiology and the perspectives in this research area are also discussed.
    Full-text · Article · Jul 2014 · Fluids and Barriers of the CNS
Show more