Parkinson Disease: Trojanowski JQ

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, Trojanowski JQ, Wszolek ZK, Anonymous00243. · Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. · Neurology. · Pubmed #17353469 No free full text.

Abstract: For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

Lee VM, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, Maloney Building, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Neuron. · Pubmed #17015225 No free full text.

Abstract: Classic Parkinson's disease (PD) is characterized by fibrillar alpha-synuclein inclusions known as Lewy bodies in the substantia nigra, which are associated with nigrostriatal degeneration. However, alpha-synuclein pathologies accumulate throughout the CNS in areas that also undergo progressive neurodegeneration, leading to dementia and other behavioral impairments in addition to parkinsonism. Although mutations in the alpha-synuclein gene only cause Lewy body PD in rare families, and although there are multiple other, albeit rare, genetic causes of familial parkinsonism, sporadic Lewy body PD is the most common movement disorder, and insights into mechanisms underlying alpha-synuclein-mediated neurodegeneration provide novel targets for the discovery of disease-modifying therapies for PD and related neurodegenerative alpha-synucleinopathies.

Forman MS, Lee VM, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania, Philadelphia, PA 19104, USA. · Neuron. · Pubmed #16102530 No free full text.

Abstract: The discovery of SNCA mutations pathogenic for autosomal-dominant Lewy body Parkinson's disease (PD) in 1997 heralded a revolution in understanding the molecular and genetic basis of PD. Indeed, it now is clear that Lewy body PD is one of many neurodegenerative parkinsonian disorders that result from nigrostriatal degeneration caused by diverse mechanisms. However, to capitalize on these new insights and facilitate efforts to improve the diagnosis and therapy of neurodegenerative movement disorders, it is timely to define a nosology for these diseases that is based on their genetic and molecular underpinnings, as proposed here.

Lee VM, Trojanowski JQ. · Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Sci Aging Knowledge Environ. · Pubmed #14573852 No free full text.

Abstract: Sponsored by the Movement Disorder Society, the 3rd International Workshop on Dementia with Lewy Bodies and Parkinson's Disease Dementia was held on 17 to 20 September 2003 in Newcastle upon Tyne, United Kingdom. This meeting report summarizes findings presented at this meeting. The presentations focused on clinicopathological correlations, therapy, genetics, and basic science research.

Van Deerlin VM, Gill LH, Farmer JM, Trojanowski JQ, Lee VM. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Health System, Philadelphia, PA 19104, USA. · Clin Chem. · Pubmed #14500612 links to  free full text

Abstract: Genetic testing is important for diagnosis and prediction of many diseases. The development of a clinical genetic test can be rapid for common disorders, but for rare genetic disorders this process can take years, if it occurs at all. We review the path from gene discovery to development of a clinical genetic test, using frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) as an example of a complex, rare genetic condition. An Institutional Review Board-approved multidisciplinary research program was developed to identify patients with familial frontotemporal dementia. Genetic counseling is provided and DNA obtained to identify mutations associated with FTDP-17. In some cases it may be appropriate for individuals to be given the opportunity to learn information from the research study to prevent unnecessary diagnostic studies or the utilization of inappropriate therapies, and to make predictive testing possible. Mutations identified in a research laboratory must be confirmed in a clinical laboratory to be used clinically. To facilitate the development of clinical genetic testing for a rare disorder, it is useful for a research laboratory to partner with a clinical laboratory. Most clinical molecular assays are developed in research laboratories and must be properly validated. We conclude that the transition of genetic testing for rare diseases from the research laboratory to the clinical laboratory requires a validation process that maintains the quality-control elements necessary for genetic testing but is flexible enough to permit testing to be developed for the benefit of patients and families.

Forman MS, Lee VM, Trojanowski JQ. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3600 Spruce Street, Maloney Building, 3rd Floor, Philadelphia, PA 19104, USA. · Trends Neurosci. · Pubmed #12900170 No free full text.

Abstract: The endoplasmic reticulum responds to stress by initiating a cascade of events known as the 'unfolded-protein response' (UPR). The accumulation of misfolded proteins in the leukodystrophy Pelizaeus-Merzbacher disease activates this stress response, resulting in apoptosis of oligodendrocytes. Although it remains uncertain whether the UPR plays a mechanistic role in prototypical neurodegenerative disorders such as Alzheimer's disease, this is plausible because misfolded proteins are directly implicated in the pathogenesis of these disorders.

Trojanowski JQ, Lee VM. · Department of Pathology, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia 19104, USA. · Neurotoxicology. · Pubmed #12428717 No free full text.

Abstract: Parkinson's disease (PD) is the most common neurodegenerative movement disorder. While the classic clinical-neuropathological features of PD have been well established, mechanisms underlying brain degeneration in PD are unknown, and only partially effective symptomatic treatments for PD exist. Further, there are no therapeutic interventions that prevent PD or block the progression of this relentless neurodegenerative disorder. However, dramatic new insights into the role of alpha-synuclein (AS) in the pathobiology of PD have emerged recently, and this has led to the development of transgenic animal models of PD-like AS pathologies. Continuing advances in this research direction should advance understanding of PD and accelerate discovery of more effective therapies for this and related synucleinopathies.

Giasson BI, Ischiropoulos H, Lee VM, Trojanowski JQ. · Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA 19104-4283, USA. · Free Radic Biol Med. · Pubmed #12057764 No free full text.

Abstract: Alzheimer's (AD) and Parkinson's diseases (PD) are late-onset neurodegenerative diseases that have tremendous impact on the lives of affected individuals, their families, and society as a whole. Remarkable efforts are being made to elucidate the dominant factors that result in the pathogenesis of these disorders. Extensive postmortem studies suggest that oxidative/nitrative stresses are prominent features of these diseases, and several animal models support this notion. Furthermore, it is likely that protein modifications resulting from oxidative/nitrative damage contribute to the formation of intracytoplasmic inclusions characteristic of each disease. The frequent presentation of both AD and PD in individuals and the co-occurrence of inclusions characteristic of AD and PD in several other neurodegenerative diseases suggests the involvement of a common underlying aberrant process. It can be surmised that oxidative/nitrative stress, which is cooperatively influenced by environmental factors, genetic predisposition, and senescence, may be a link between these disorders.

Galvin JE, Lee VM, Trojanowski JQ. · Alzheimer's Disease Research Center, Department of Neurology, Campus Box 8111, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110, USA. · Arch Neurol. · Pubmed #11176955 links to  free full text

Abstract: The synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathologic lesion composed of aggregates of insoluble alpha-synuclein protein in selectively vulnerable populations of neurons and glia. Growing evidence links the formation of abnormal filamentous aggregates to the onset and progression of clinical symptoms and the degeneration of affected brain regions in neurodegenerative disorders. These disorders may share an enigmatic symmetry, i.e., missense mutations in the gene encoding for the disease protein (alpha-synuclein) cause familial variants of Parkinson disease as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild-type brain protein in the more common sporadic varieties of Parkinson disease. It is likely that clarification of this enigmatic symmetry in 1 form of synucleinopathy will have a profound impact on understanding the mechanisms underlying all these disorders. Furthermore, these efforts will likely lead to novel diagnostic and therapeutic strategies in regard to the synucleinopathies.

Galvin JE, Lee VM, Schmidt ML, Tu PH, Iwatsubo T, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA. · Adv Neurol. · Pubmed #10410736 No free full text.

This publication has no abstract.

Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S. · Division of Clinical Pharmacology, University of Colorado School of Medicine, Denver 80262, USA. · N Engl J Med. · Pubmed #11236774 links to  free full text

Abstract: BACKGROUND: Transplantation of human embryonic dopamine neurons into the brains of patients with Parkinson's disease has proved beneficial in open clinical trials. However, whether this intervention would be more effective than sham surgery in a controlled trial is not known. METHODS: We randomly assigned 40 patients who were 34 to 75 years of age and had severe Parkinson's disease (mean duration, 14 years) to receive a transplant of nerve cells or sham surgery; all were to be followed in a double-blind manner for one year. In the transplant recipients, cultured mesencephalic tissue from four embryos was implanted into the putamen bilaterally. In the patients who received sham surgery, holes were drilled in the skull but the dura was not penetrated. The primary outcome was a subjective global rating of the change in the severity of disease, scored on a scale of -3.0 to 3.0 at one year, with negative scores indicating a worsening of symptoms and positive scores an improvement. RESULTS: The mean (+/-SD) scores on the global rating scale for improvement or deterioration at one year were 0.0+/-2.1 in the transplantation group and -0.4+/-1.7 in the sham-surgery group. Among younger patients (60 years old or younger), standardized tests of Parkinson's disease revealed significant improvement in the transplantation group as compared with the sham-surgery group when patients were tested in the morning before receiving medication (P=0.01 for scores on the Unified Parkinson's Disease Rating Scale; P=0.006 for the Schwab and England score). There was no significant improvement in older patients in the transplantation group. Fiber outgrowth from the transplanted neurons was detected in 17 of the 20 patients in the transplantation group, as indicated by an increase in 18F-fluorodopa uptake on positron-emission tomography or postmortem examination. After improvement in the first year, dystonia and dyskinesias recurred in 15 percent of the patients who received transplants, even after reduction or discontinuation of the dose of levodopa. CONCLUSIONS: Human embryonic dopamine-neuron transplants survive in patients with severe Parkinson's disease and result in some clinical benefit in younger but not in older patients.

Mendez I, Viñuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O. · Dalhousie University and Queen Elizabeth II Health Sciences Centre, Division of Neurosurgery and Department of Anatomy & Neurobiology, 1976 Summer Street, Halifax, Nova Scotia B3H 3A7, Canada. · Nat Med. · Pubmed #18391961 links to  free full text

Abstract: Postmortem analysis of five subjects with Parkinson's disease 9-14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis of midbrain dopamine neuron degeneration and future use of cell replacement therapies.

Soper JH, Roy S, Stieber A, Lee E, Wilson RB, Trojanowski JQ, Burd CG, Lee VM. · Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Mol Biol Cell. · Pubmed #18172022 links to  free full text

Abstract: Aggregated alpha-synuclein (alpha-syn) fibrils form Lewy bodies (LBs), the signature lesions of Parkinson's disease (PD) and related synucleinopathies, but the pathogenesis and neurodegenerative effects of LBs remain enigmatic. Recent studies have shown that when overexpressed in Saccharomyces cerevisiae, alpha-syn localizes to plasma membranes and forms cytoplasmic accumulations similar to human alpha-syn inclusions. However, the exact nature, composition, temporal evolution, and underlying mechanisms of yeast alpha-syn accumulations and their relevance to human synucleinopathies are unknown. Here we provide ultrastructural evidence that alpha-syn accumulations are not comprised of LB-like fibrils, but are associated with clusters of vesicles. Live-cell imaging showed alpha-syn initially localized to the plasma membrane and subsequently formed accumulations in association with vesicles. Imaging of truncated and mutant forms of alpha-syn revealed the molecular determinants and vesicular trafficking pathways underlying this pathological process. Because vesicular clustering is also found in LB-containing neurons of PD brains, alpha-syn-mediated vesicular accumulation in yeast represents a model system to study specific aspects of neurodegeneration in PD and related synucleinopathies.

Chen-Plotkin AS, Yuan W, Anderson C, McCarty Wood E, Hurtig HI, Clark CM, Miller BL, Lee VM, Trojanowski JQ, Grossman M, Van Deerlin VM. · Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine, University of Pennsylvania Health System, Philadelphia, PA 19104, USA. · Neurology. · Pubmed #17914064 No free full text.

Abstract: BACKGROUND: Mutations in the LRRK2 gene are an important cause of familial and nonfamilial parkinsonism. Despite pleomorphic pathology, LRRK2 mutations are believed to manifest clinically as typical Parkinson disease (PD). However, most genetic screens have been limited to PD clinic populations. OBJECTIVE: To clinically characterize LRRK2 mutations in cases recruited from a spectrum of neurodegenerative diseases. METHODS: We screened for the common G2019S mutation and several additional previously reported LRRK2 mutations in 434 individuals. A total of 254 patients recruited from neurodegenerative disease clinics and 180 neurodegenerative disease autopsy cases from the University of Pennsylvania brain bank were evaluated. RESULTS: Eight cases were found to harbor a LRRK2 mutation. Among patients with a mutation, two presented with cognitive deficits leading to clinical diagnoses of corticobasal syndrome and primary progressive aphasia. CONCLUSION: The clinical presentation of LRRK2-associated neurodegenerative disease may be more heterogeneous than previously assumed.

Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, Arnold SE, Siderowf A, Grossman M, Leverenz JB, Woltjer R, Lopez OL, Hamilton R, Tsuang DW, Galasko D, Masliah E, Kaye J, Clark CM, Montine TJ, Lee VM, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP/Maloney 3rd Floor, Philadelphia, PA 19104-4283, USA. · Acta Neuropathol. · Pubmed #17653732 No free full text.

Abstract: Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

Norris EH, Uryu K, Leight S, Giasson BI, Trojanowski JQ, Lee VM. · Center for Neurodegenerative Disease Research, Institute on Aging, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce St., Maloney 3, HUP, Philadelphia, PA 19104-4283, USA. · Am J Pathol. · Pubmed #17255333 links to  free full text

Abstract: The factors initiating or contributing to the pathogenesis of Parkinson's disease and related neurodegenerative synucleinopathies are still largely unclear, but environmental factors such as pesticides have been implicated. In this study, A53T mutant human alpha-synuclein transgenic mice (M83), which develop alpha-synuclein neuropathology, were treated with the pesticides paraquat and maneb (either singly or together), and their effects were analyzed. Immunohistochemical and biochemical analyses showed that chronic treatment of M83 transgenic mice with both pesticides (but not with either pesticide alone) drastically increased neuronal alpha-synuclein pathology throughout the central nervous system including the hippocampus, cerebellum, and sensory and auditory cortices. alpha-Synuclein-associated mitochondrial degeneration was observed in M83 but not in wild-type alpha-synuclein transgenic mice. Because alpha-synuclein inclusions accumulated in pesticide-exposed M83 transgenic mice without a motor phenotype, we conclude that alpha-synuclein aggregate formation precedes disease onset. These studies support the notion that environmental factors causing nitrative damage are closely linked to mechanisms underlying the formation of alpha-synuclein pathologies and the onset of Parkinson's-like neurodegeneration.

Fan Y, Limprasert P, Murray IV, Smith AC, Lee VM, Trojanowski JQ, Sopher BL, La Spada AR. · Department of Laboratory Medicine, University of Washington Medical Center, Seattle, WA, USA. · Hum Mol Genet. · Pubmed #16959793 links to  free full text

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of alpha-synuclein in characteristic inclusions known as "Lewy bodies". As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial forms of PD or related Lewy body disorders, alpha-synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in "synucleinopathies". beta-synuclein is closely related to alpha-synuclein and has been shown to inhibit alpha-synuclein aggregation and ameliorate alpha-synuclein neurotoxicity. We generated beta-synuclein transgenic mice and observed a marked reduction in alpha-synuclein protein expression in the cortex of mice over-expressing beta-synuclein. This reduction in alpha-synuclein protein expression was not accompanied by decreases in alpha-synuclein mRNA expression. Using the prion protein promoter alpha-synuclein A53T mouse model of PD, we demonstrated that over-expression of beta-synuclein could retard the progression of impaired motor performance, reduce alpha-synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of alpha-synuclein neurotoxicity in such bigenic mice to the ability of beta-synuclein to reduce alpha-synuclein protein expression based upon I(125) autoradiography quantification. Our findings indicate that increased expression of beta-synuclein protein results in a reduction of alpha-synuclein protein expression. As increased expression of alpha-synuclein may cause or contribute to PD pathogenesis in sporadic and familial forms of disease, this observation has important implications for the development of therapies for PD.

Goker-Alpan O, Giasson BI, Eblan MJ, Nguyen J, Hurtig HI, Lee VM, Trojanowski JQ, Sidransky E. · Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892-3708, USA. · Neurology. · Pubmed #16790605 No free full text.

Abstract: The synucleinopathies are neurodegenerative disorders defined by inclusions composed of aberrantly fibrillized alpha-synuclein, but factors contributing to this process remain largely unknown. The authors examined the glucocerebrosidase gene in 75 autopsy specimens with different synucleinopathies and identified mutations in 23% of cases of dementia with Lewy bodies, expanding on previous findings in subjects with Parkinson disease. Mutations in this lysosomal protein may interfere with the clearance or promote aggregation of alpha-synuclein.

Winton MJ, Joyce S, Zhukareva V, Practico D, Perl DP, Galasko D, Craig U, Trojanowski JQ, Lee VM. · The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA. · Acta Neuropathol. · Pubmed #16609851 No free full text.

Abstract: Guam parkinsonism-dementia complex (PDC) is a neurodegenerative tauopathy in ethnic Chamorro residents of the Mariana Islands that manifests clinically with parkinsonism as well as dementia and is characterized neuropathologically by prominent cortical neuron loss in association with extensive telencephalic neurofibrillary tau pathology. To further characterize cortical gray and white matter tau, alpha-synuclein and lipid peroxidation pathologies in Guam PDC, we examined the brains of 17 Chamorro PDC and control subjects using biochemical and immunohistological techniques. We observed insoluble tau pathology in both gray and white matter of PDC and Guam control cases, with frontal and temporal lobes being most severely affected. Using phosphorylation dependent anti-tau antibodies, abundant tau inclusions were detected by immunohistochemistry in both neuronal and glial cells of the neocortex, while less alpha-synuclein pathology was observed in more limited brain regions. Further, in sharp contrast to Alzheimer's disease (AD), levels of the lipid peroxidation product 8, 12-iso-iPF(2alpha)-VI isoprostane were not elevated in Guam PDC brains relative to controls. Thus, although the tau pathologies of Guam PDC share similarities with AD, the composite Guam PDC neuropathology profile of tau, alpha-synuclein and 8, 12-iso-iPF(2alpha)-VI isoprostane reported here more closely resembles that seen in other tauopathies including frontotemporal dementias (FTDs), which may imply that Guam PDC and FTD tauopathies share underlying mechanisms of neurodegeneration.

Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ, Van Deerlin VM. · Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA. · Ann Neurol. · Pubmed #16437584 No free full text.

Abstract: OBJECTIVE: Mutations in leucine-rich repeat kinase 2 (LRRK2) recently have been identified as the most common genetic cause of late-onset sporadic and familial Parkinson's disease (PD). The studies herein explore the biological and pathological properties of Lrrk2. METHODS: Genetic analysis was performed to identify autopsied patients with the most common Lrrk2 mutation (G2019S). Using an antibody specific to Lrrk2, the biochemical and immunocytochemical distribution of Lrrk2 was assessed. RESULTS: Three patients with the G2019S Lrrk2 mutation were identified. Two patients demonstrated classic PD with Lewy bodies, although concurrent pathological changes consistent with Alzheimer's disease were also present in one of these individuals. The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2. Lrrk2 accumulations were unique to this patient and Lrrk2 was not detected in other types of pathological inclusions. Biochemical analysis showed that Lrrk2 is predominantly a soluble approximately 250 kDa cytoplasmic protein expressed throughout the brain but also in many other organs. INTERPRETATION: The reasons for the selective predisposition of patients with mutations in LRRK2 to develop parkinsonism remains unclear, but Lrrk2 mutations may prime select neuronal populations to cellular insults that can lead to aberrant protein aggregation.

Mishizen-Eberz AJ, Norris EH, Giasson BI, Hodara R, Ischiropoulos H, Lee VM, Trojanowski JQ, Lynch DR. · Department of Neurology, University of Pennsylvania and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. · Biochemistry. · Pubmed #15909996 No free full text.

Abstract: Alpha-synuclein (alpha-syn) is a major protein component of the neuropathological hallmarks of Parkinson's disease and related neurodegenerative disorders termed synucleinopathies. Neither the mechanism of alpha-syn fibrillization nor the degradative process for alpha-syn has been elucidated. Previously, we showed that wild-type, mutated, and fibrillar alpha-syn proteins are substrates of calpain I in vitro. In this study, we demonstrate that calpain-mediated cleavage near and within the middle region of soluble alpha-syn with/without tyrosine nitration and oxidation generates fragments that are unable to self-fibrillize. More importantly, these fragments prevent full-length alpha-syn from fibrillizing. Calpain-mediated cleavage of alpha-syn fibrils composed of wild-type or nitrated alpha-syn generate C-terminally truncated fragments that retain their fibrillar structure and induce soluble full-length alpha-syn to co-assemble. Therefore, calpain-cleaved soluble alpha-syn inhibits fibrillization, whereas calpain-cleaved fibrillar alpha-syn promotes further co-assembly. These results provide insight into possible disease mechanisms underlying synucleinopathies since the formation of alpha-syn fibrils could be causally linked to the onset/progression of these disorders.

Norris EH, Giasson BI, Hodara R, Xu S, Trojanowski JQ, Ischiropoulos H, Lee VM. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · J Biol Chem. · Pubmed #15817478 links to  free full text

Abstract: Previous studies demonstrated that alpha-synuclein (alpha-syn) fibrillization is inhibited by dopamine, and studies to understand the molecular basis of this process were conducted (Conway, K. A., Rochet, J. C., Bieganski, R. M., and Lansbury, P. T., Jr. (2001) Science 294, 1346-1349). Dopamine inhibition of alpha-syn fibrillization generated exclusively spherical oligomers that depended on dopamine autoxidation but not alpha-syn oxidation, because mutagenesis of Met, His, and Tyr residues in alpha-syn did not abrogate this inhibition. However, truncation of alpha-syn at residue 125 restored the ability of alpha-syn to fibrillize in the presence of dopamine. Mutagenesis and competition studies with specific synthetic peptides identified alpha-syn residues 125-129 (i.e. YEMPS) as an important region in the dopamine-induced inhibition of alpha-syn fibrillization. Significantly, the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of alpha-syn fibrillization. Dopaminochrome promotes the formation of spherical oligomers by inducing conformational changes, as these oligomers regained the ability to fibrillize by simple denaturation/renaturation. Taken together, these data indicate that dopamine inhibits alpha-syn fibrillization by inducing structural changes in alpha-syn that can occur through the interaction of dopaminochrome with the 125YEMPS129 motif of alpha-syn. These results suggest that the dopamine autoxidation can prevent alpha-syn fibrillization in dopaminergic neurons through a novel mechanism. Thus, decreased dopamine levels in substantia nigra neurons might promote alpha-syn aggregation in Parkinson's disease.

Liang TW, Forman MS, Duda JE, McCluskey L, Trojanowski JQ, Siderowf A. · Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #15654043 links to  free full text

Abstract: A woman presenting with levodopa responsive Parkinsonism developed rapidly progressive bulbar signs, quadriparesis, and upper and lower motor neurone signs. At necropsy, she was found to have three pathological diagnoses: amyotrophic lateral sclerosis, Parkinson's disease, and abundant tau-positive argyrophilic neuritic pathology, known as argyrophilic grain disease. This case raises the possibility that three distinct neuropathological diagnoses share a common aetiology.

Ohtake H, Limprasert P, Fan Y, Onodera O, Kakita A, Takahashi H, Bonner LT, Tsuang DW, Murray IV, Lee VM, Trojanowski JQ, Ishikawa A, Idezuka J, Murata M, Toda T, Bird TD, Leverenz JB, Tsuji S, La Spada AR. · Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan. · Neurology. · Pubmed #15365127 links to  free full text

Abstract: OBJECTIVE: To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD). METHODS: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity. RESULTS: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation. CONCLUSION: Mutations in the beta-synuclein gene may predispose to DLB.