A-Synuclein

Diffuse Lewy body Cerebrocortical regions, a-Synuclein Lewy bodies and neurites... 

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

Mice expressing high levels of human a-synuclein under the control of the human PDGF(5 promoter developed intracellular nuclear... 

Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PT, Goedert M. Filamentous a-synuclein inclusions link multiple system atrophy with Parkinson s disease and dementia with Lewy bodies. Neurosci Lett 1998 251 205-208. 

The conformational plasticity supported by mobile regions within native proteins, partially denatured protein states such as molten globules, and natively unfolded proteins underlies many of the conformational (protein misfolding) diseases (Carrell and Lomas, 1997 Dobson et al., 2001). Many of these diseases involve amyloid fibril formation, as in amyloidosis from mutant human lysozymes, neurodegenerative diseases such as Parkinson s and Alzheimer s due to the hbrillogenic propensities of a -synuclein and tau, and the prion encephalopathies such as scrapie, BSE, and new variant Creutzfeldt-Jacob disease (CJD) where amyloid fibril formation is triggered by exposure to the amyloid form of the prion protein. In addition, aggregation of serine protease inhibitors such as a j-antitrypsin is responsible for diseases such as emphysema and cirrhosis. 

The failure of proteins to fold into their functional forms can occasionally lead to "misfolding" or "conformational" diseases.140 Many of these diseases are associated with the formation of amyloid protein, an insoluble material that is deposited as fibrils or plaques in different tissues and organs of the body. They include amyloid Ap protein as the major constituent of the plaques in Alzheimer patients, PrPc associated with neuro-degenerative diseases, a-synuclein (AS) associated with Parkinson s diseases, transthyretin (TTR) as a homotetrameric protein that is involved in the transport of thyroid hormones and retinol in human serum. In particular, the Ap protein is a peptide of 39-43 amino acids that is the... 

The use of pairs of matched spectral variants of GFP, like cyan and yellow or GFP and mRed, to differentially tag proteins and look for interactions, is now in routine use. The approach can be readily applied to homodimerization of molecules that differ only by their living color or epitope tag. For example, homomultimer-ization of a viral coat protein can be observed by imaging a mixture of cyan and yellow tagged homomeric molecules [46], whereas oc-synuclein stacking can be detected by utilizing a-synuclein transcripts that encoded different epitope tags for detection by immunostaining [47],... 

Roberti, M. J., Morgan, M., Pietrasanta, L., Jovin, T. M. and Jares-Erijman, E. A. (2008). Quantum dots as efficient triggers-sensors of a-synuclein amyloid aggregation in living cells, submitted. 

Fig. 8 Pulse sequence for the measurement of homonuclear correlation spectra with 7 filtering. Narrows bars indicate 7t/2 pulses and broad bars indicate 71 pulses. Experimental conditions employed for a-synuclein fibrils samples static field strength 9.4 T temperature —5 °C spinning frequency 8 kHz T2 filter 100 ms CP contact time 2.5 ms TOBSY mixing time 6 ms. The rf phases can be found in the original figure and caption. (Figure and caption adapted from the Supporting Information of [134]. Copyright (2005) National Academy of Sciences, USA)...

SNCA a-synuclein 4q21 Dominant Neurotoxicity by aggregation of a-synuclein ( )... 

Filamentous a-synuclein deposits characterize this atypical parkinsonian... 

Lewy bodies, neurofibrillary lesions and Pick bodies are intracellular filamentous inclusions. It is now well established that Lewy bodies are made of the protein a-synuclein and both neurofibrillary lesions and Pick bodies of the microtubule-associated protein tau. Mutations in the a-synuclein gene or an increase in its copy number cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. Mutations in the tau gene cause a familial form of frontotemporal dementia. Here we review the evidence implicating a-synuclein and tau in these inherited and a number of sporadic neurodegenerative diseases. Collectively, a-synucleinopathies and tauopathies account for the vast majority of cases of late-onset neurodegenerative disease (Tables 45-1 and 45-2). 

TABLE 45-1 a-Synuclein diseases Idiopathic Parkinson s disease Dementia with Lewy bodies Pure autonomic failure REM sleep behavior disorder Lewy body dysphagia Incidental Lewy body disease Inherited Lewy body diseases Multiple system atrophy... 

By immunohistochemistry, a- and p-synucleins are concentrated in nerve terminals, with little staining of somata and dendrites. Ultrastructurally, they are found in close proximity to synaptic vesicles. In contrast,y-synuclein is present throughout nerve cells in many brain regions. In rat, a-synuclein is most abundant throughout telencephalon and diencephalon, with lower levels in more caudal regions. P-Synuclein is distributed fairly evenly throughout the central nervous system, whereas y-synuclein is most abundant in midbrain, pons and spinal cord, with much lower levels in forebrain areas. 

Inactivation of the a-synuclein gene by homologous recombination results in mice that appear largely normal [3]. Analysis of mice lacking y-synuclein has similarly failed to reveal any gross abnormalities [4]. In hippocampal slices from mice without a-synuclein, the replenishment of docked vesicles by reserve pool vesicles was slower than in slices from control mice. It suggests a physiological role for a-synuclein in the mobilization of synaptic vesicles. 

E46K) was described in a Spanish family with Parkinson s disease and dementia with Lewy bodies. All three missense mutations are located in the repeat region of a-synuclein (Fig. 45-1 and Fig. 45-2). 

Lewy body filaments are made of a-synuclein. Shortly after the identification of the genetic defect responsible for Parkinson s disease in the Contursi kindred, Lewy bodies and Lewy neurites in the substantia nigra from patients with sporadic Parkinson s disease were shown to be strongly immunoreactive for a-synuclein [7] (Fig. 45-3). Subsequently, Lewy body filaments were found to be... 

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