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.

12 Reads
  • 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.
    Fluids and Barriers of the CNS 07/2014; 11(1):17. DOI:10.1186/2045-8118-11-17
  • Source
    • "However, when these defense systems fail to repair, protein aggregates accumulate and induce cell death [5]. Parkinson's disease (PD) is known to associated with formation of protein aggregates and Lewy bodies as hallmarks of PD [9], [10]. Although there is evidence that protein aggregates are toxic to cells [11], [12], it is not a necessary and sufficient condition to develop PD in human patients and animal models [13]–[15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ubiquitin C-terminal hydrolase-L1 (UCH-L1) has been proposed as one of the Parkinson's disease (PD) related genes, but the possible molecular connection between UCH-L1 and PD is not well understood. In this study, we discovered an N-terminal 11 amino acid truncated variant UCH-L1 that we called NT-UCH-L1, in mouse brain tissue as well as in NCI-H157 lung cancer and SH-SY5Y neuroblastoma cell lines. In vivo experiments and hydrogen-deuterium exchange (HDX) with tandem mass spectrometry (MS) studies showed that NT-UCH-L1 is readily aggregated and degraded, and has more flexible structure than UCH-L1. Post-translational modifications including monoubiquitination and disulfide crosslinking regulate the stability and cellular localization of NT-UCH-L1, as confirmed by mutational and proteomic studies. Stable expression of NT-UCH-L1 decreases cellular ROS levels and protects cells from H2O2, rotenone and CCCP-induced cell death. NT-UCH-L1-expressing transgenic mice are less susceptible to degeneration of nigrostriatal dopaminergic neurons seen in the MPTP mouse model of PD, in comparison to control animals. These results suggest that NT-UCH-L1 may have the potential to prevent neural damage in diseases like PD.
    PLoS ONE 06/2014; 9(6):e99654. DOI:10.1371/journal.pone.0099654 · 3.23 Impact Factor
  • Source
    • "On the basis of these results, the phenotypes of our patients seemed to be different from those of iPD patients with Lewy pathology. Pathologic findings in PD patients with LRRK2 mutations are very variable despite them exhibiting a relatively uniform clinical phenotype of parkinsonism (Cookson et al., 2008; Hasegawa et al., 2009; Ross et al., 2006; Ujiie et al., 2012; Zimplich et al., 2004). A clinicopathological study of patients with the p.G2019S mutation revealed no correlation between Lewy pathology and clinical phenotypes, including dementia and psychiatric symptoms (Ross et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) is a causative gene of autosomal dominant familial Parkinson's disease (PD). We screened for LRRK2 mutations in 3 frequently reported exons (31, 41, and 48) in our cohort of 871 Japanese patients with PD (430 with sporadic PD and 441 probands with familial PD). Direct sequencing analysis of LRRK2 revealed 1 proband (0.11%) with a p.R1441G mutation, identified for the first time in Asian countries, besides frequently reported substitutions including, the p.G2019S mutation (0.11%) and p.G2385R variant (11.37%). Several studies have suggested that the LRRK2 p.R1441G mutation, which is highly prevalent in the Basque country, is extremely rare outside of northern Spain. Further analysis of family members of the proband with the p.R1441G mutation revealed that her mother and first cousin shared the same mutation and parkinsonism. Haplotype analysis revealed a different haplotype from that of the original Spanish families. Our patients demonstrated levodopa-responsive parkinsonism with intrafamilial clinical heterogeneity. This is the first report of familial PD because of the LRRK2 p.R1441G mutation in Asia.
    Neurobiology of Aging 06/2014; 35(11). DOI:10.1016/j.neurobiolaging.2014.05.025 · 5.01 Impact Factor
Show more


12 Reads
Available from