Скачать или смотреть Alpha synuclein (transglutaminase substrate) Facheris&Harvard&Ahmed

FOTGCREN HYPOTHESIS:
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GROSSO 2014:
https://www.ncbi.nlm.nih.gov/pubmed/2...

α-Synuclein is a key protein in the pathogenesis of Parkinson’s disease (PD), based on genetic, neuro-pathologic, and cellular/molecular lines of evidence.

The 140-residue α-Synuclein peptide is natively unfolded but forms oligomers of β -pleated sheets called protofibrils, which can proceed to form amyloid fibrils in response to diverse exogenous and endoge-nous factors. Evidence for a deleterious effect of both the protofibrillar aggregates and the mature inclusions has been generated. Thus, elucidating the factors that promote α-Synuclein aggregation, particularly those that act early in the process, has the potential to lead to rational approaches toward neuroprotection.

Transglutaminase 2 (TG2) is one of these factors implicated in PD, as well as in other neurodegenerative diseases characterized by protein misfolding. It is expressed in many brain regions including the cortex, hippocampus, and substantia nigra, primarily in neurons but also in glial cells.

While TG2 has several enzymatic activities and cell biological functions, its transamidation activity, which cross-links proteins between glutamine and lysine residues creating inter- or intramolecular covalent bonds, has been studied the most in relation to protein aggregation disorders.

Among its substrates to form these isopeptide bonds that are highly resistant to proteolysis are α-Synuclein, huntingtin, tau, and Aβ peptide, demonstrated in in vitro and cell-based experiments.

TG2-mediated cross-linking has been shown to alter the aggregation pathway of α-Synuclein, potentially resulting in a more toxic form.

In addition, evidence for increased TG2 activity has been found in patients with these disorders.

In PD, there is increased TG2 protein and mRNA expression in the substantia nigra and increased TG2 protein levels in the cerebrospinal fluid.

In addition, the isopeptide bonds formed by TG2 colocalize with α-Synuclein immunoreactivity in Lewy bodies in PD- and dementia with Lewy bodies (DLB)-affected brains, and the 2 proteins coimmunoprecipitate in lysates of the substantia nigra from patients with PD.

While all these provide circumstantial evidence for the role of TG2 in the pathology of α-synucleinopathies, cross-linking of α-synuclein by TG2 in vivo has not yet been demonstrated nor is there direct evidence for a toxic role of this interaction.

Here, we demonstrate that increased expression of TG2 in vivo does lead to increased α-Synuclein aggregation and that this function is associated with exacerbated toxicity of α-Synuclein in the mouse brain as well as in yeast cells.