Differential regulation of wild-type and mutant alpha-synuclein binding to synaptic membranes by cytosolic factors

BACKGROUND: Alpha-Synuclein (alpha-syn), a 140 amino acid protein associated with presynaptic membranes in brain, is a major constituent of Lewy bodies in Parkinson's disease (PD). Three missense mutations (A30P, A53T and E46K) in the alpha-syn gene are associated with rare autosomal dominant forms of familial PD. However, the regulation of alpha-syn's cellular localization in neurons and the effects of the PD-linked mutations are poorly understood. RESULTS: In the present study, we analysed the ability of cytosolic factors to regulate alpha-syn binding to synaptic membranes. We show that co-incubation with brain cytosol significantly increases the membrane binding of normal and PD-linked mutant alpha-syn. To characterize cytosolic factor(s) that modulate alpha-syn binding properties, we investigated the ability of proteins, lipids, ATP and calcium to modulate alpha-syn membrane interactions. We report that lipids and ATP are two of the principal cytosolic components that modulate Wt and A53T alpha-syn binding to the synaptic membrane. We further show that 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) is one of the principal lipids found in complex with cytosolic proteins and is required to enhance alpha-syn interaction with synaptic membrane. In addition, the impaired membrane binding observed for A30P alpha-syn was significantly mitigated by the presence of protease-sensitive factors in brain cytosol. CONCLUSION: These findings suggest that endogenous brain cytosolic factors regulate Wt and mutant alpha-syn membrane binding, and could represent potential targets to influence alpha-syn solubility in brain

The infrastructural power of the military: The geoeconomic role of the US Army Corps of Engineers in the Arabian Peninsula

In analysing the role of the US in the global expansion of capitalist relations, most critical accounts see the US military’s invasion and conquest of various states as paving the way for the arrival of US businesses and capitalist relations. However, beyond this somewhat simplified image, and even in peacetime, the US military has been a major geoeconomic actor that has wielded its infrastructural power via its US Army Corps of Engineers’ overseas activities. The transformation of global economies in the 20th century has depended on the capitalisation of the newly independent states and the consolidation of liberal capitalist relations in the subsequent decades. The US Army Corps of Engineers has not only extended lucrative contracts to private firms (based not only in the US and host country, but also in geopolitically allied states), but also, and perhaps most important, has itself established a grammar of capitalist relations. It has done so by forging both physical infrastructures (roads, ports, utilities and telecommunications infrastructures) and virtual capitalist infrastructures through its practices of contracting, purchasing, design, accounting, regulatory processes and specific regimes of labour and private property ownership

Knowledge gaps and research recommendations for essential tremor

Essential tremor (ET) is a common cause of significant disability, but its etiologies and pathogenesis are poorly understood. Research has been hampered by the variable definition of ET and by non-standardized research approaches. The National Institute of Neurological Disorders and Stroke (USA) invited experts in ET and related fields to discuss current knowledge, controversies, and gaps in our understanding of ET and to develop recommendations for future research. Discussion focused on phenomenology and phenotypes, therapies and clinical trials, pathophysiology, pathology, and genetics. Across all areas, the need for collaborative and coordinated research on a multinational level was expressed. Standardized data collection using common data elements for genetic, clinical, neurophysiological, and pathological studies was recommended. Large cohorts of patients should be studied prospectively to collect bio-samples, characterize the natural history of the clinical syndrome including patient-oriented outcomes, investigate potential etiologies of various phenotypes, and identify pathophysiological mechanisms. In particular, cellular and system-level mechanisms of tremor oscillations should be elucidated because they may yield effective therapeutic targets and biomarkers. A neuropathology consortium was recommended to standardize postmortem analysis and further characterize neuropathological observations in the cerebellum and elsewhere. Furthermore, genome-wide association studies on large patient cohorts (>10,000 patients) may allow the identification of common genes contributing to risk, and whole exome or genome sequencing may enable the identification of genetic risk and causal mutations in cohorts and well-characterized families

Recommendations of the Global Multiple System Atrophy Research Roadmap Meeting

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided

Evaluating the relationship between amyloid-β and α-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson’s disease

INTRODUCTION: Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and α-synuclein (α-syn) accumulation. We have explored the relationship between Aβ accumulation and the phosphorylation of α-syn at serine-129 (pSer129 α-syn), in post-mortem human brain tissue and in SH-SY5Y neuroblastoma cells transfected to overexpress human α-syn. METHODS: We measured levels of Aβ40, Aβ42, α-syn and pSer129 α-syn by sandwich enzyme-linked immunosorbent assay, in soluble and insoluble fractions of midfrontal, cingulate and parahippocampal cortex and thalamus, from cases of Parkinson’s disease (PD) with (PDD; n = 12) and without dementia (PDND; n = 23), dementia with Lewy bodies (DLB; n = 10) and age-matched controls (n = 17). We also examined the relationship of these measurements to cognitive decline, as measured by time-to-dementia and the mini-mental state examination (MMSE) score in the PD patients, and to Braak tangle stage. RESULTS: In most brain regions, the concentration of insoluble pSer129 α-syn correlated positively, and soluble pSer129 α-syn negatively, with the levels of soluble and insoluble Aβ. Insoluble pSer129 α-syn also correlated positively with Braak stage. In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains. In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn. Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect). CONCLUSIONS: Together, these data show that the concentration of pSer129 α-syn in brain tissue homogenates is directly related to the level of Aβ and Braak tangle stage, and predicts cognitive status in Lewy body diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-014-0077-y) contains supplementary material, which is available to authorized users

Xenotransplantation of porcine fetal ventral mesencephalon in a rat model of Parkinson\u27s disease: functional recovery and graft morphology

Neurotransplantation of human fetal dopamine (DA) neurons is currently being investigated as a therapeutic modality for Parkinson\u27s disease (PD). However, the practical limitations of human fetal transplantation indicate a need for alternative methodologies. Using the 6-hydroxydopamine rat model of PD, we transplanted dopaminergic neurons derived from Embryonic Day 27 porcine fetuses into the denervated striatum of cyclosporine-A (CyA)-treated or non-CyA-treated rats. Functional recovery was assessed by amphetamine-induced rotation, and graft survival and morphology were analyzed using neuronal and glial immunostaining as well as in situ hybridization with a porcine repeat element DNA probe. A significant, sustained reduction in amphetamine-induced rotational asymmetry was present in the CyA-treated rats whereas the non-CyA-treated rats showed a transient behavioral recovery. The degree of rotational recovery was highly correlated to the number of surviving transplanted porcine dopaminergic neurons. TH+ neuronal survival and graft volume were significantly greater in the CyA-treated group as compared to the non-CyA group. By donor-specific neuronal and glial immunostaining as well as donor-specific DNA labeling, we demonstrate that porcine fetal neuroblasts are able to survive in the adult brain of immunosuppressed rats, mediate functional recovery, and extensively reinnervate the host striatum. These findings suggest that porcine DA neurons may be a suitable alternative to the use of human fetal tissue in neurotransplantation for PD

Transplanted xenogeneic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibres

Clinical trials are under way using fetal cells to repair damaged neuronal circuitry. However, little is known about how transplanted immature neurons can grow anatomically correct connections in the adult central nervous system (CNS). We transplanted embryonic porcine neural cells in vivo into adult rat brains with neuronal and axonal loss typical of Parkinson\u27s or Huntington\u27s disease. Using complementary species-specific cellular markers, we found donor axons and CD44+ astroglial fibres in host white matter tracts up to 8 mm from CNS transplant sites, although only donor axons were capable of reaching correct gray matter target regions. This work demonstrates that adult host brain can orient growth of transplanted neurons and that there are differences in transplant donor glial and axonal growth patterns in cellular repair of the mature CNS

Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat.

The trophism of brain-derived neurotrophic factor (BDNF) for dopaminergic cells in culture has led to significant interest in the role of BDNF in the etiology and potential treatment of Parkinson disease. Previous in vivo investigation of BDNF delivery to axotomized substantia nigra dopaminergic neurons in the adult rat has shown no protective effect. In this study, we produced nigral degeneration by infusing 1-methyl-4-phenylpyridinium (MPP+), a mitochondrial complex I inhibitor and the active metabolite of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), into the rat striatum. The subsequent loss of nigral neurons was presumably due to mitochondrial toxicity after MPP+ uptake and retrograde transport to the substantia nigra. We engineered immortalized rat fibroblasts to secrete human BDNF and implanted these cells near the substantia nigra 7 days before striatal MPP+ infusion. We found that BDNF-secreting fibroblasts markedly increased nigral dopaminergic neuronal survival when compared to control fibroblast implants. The observation that BDNF prevents MPTP-induced dopaminergic neuronal degeneration in the adult brain has significance for the treatment of neurodegenerative disorders, which may involve mitochondrial dysfunction, such as Parkinson disease