Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alanine-to-threonine (A to T) substitutions caused by single nucleotide polymorphisms (SNPs) occur in diverse proteins, and in certain cases these substitutions induce self-aggregation into amyloid fibrils or aggregation in other amyloidogenic proteins. This is compatible with the inverse preferences of alanine to form helices and of threonine to support beta-sheet structures, which are crucial for amyloid fibrils formation. Our interest in these mutations was initiated by studying the potential effects of the A539T substitution in the butyrylcholinesterase BChE-K variant on amyloid fibrils formation in Alzheimer's disease. Other examples are, Parkinson's disease (PD), where A53T alpha-synuclein occurs in Lewy bodies and familial amyloid polyneuropathy (FAP), where an A25T substitution appears in transthyretin (TTR). In peripheral organs, an A34T substitution is found in the light chain immunoglobulin genes of patients with systemic amyloidosis and in familial hypercholesterolemia, an A370T substitution occurs in the LDLR regulator of cholesterol homeostasis. That such substitutions appear in proteins with important cellular functions suggests that they confer antagonistic pleiotropy, providing added value at an earlier age but causing damages and inducing amyloid diseases later on. This, in turn, may explain the evolutionary selection and preservation of these substitutions. The structural effect of residue substitutions and in particular A to T substitutions in amyloidogenic diseases thus merits further attention.
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PMID:Alanine-to-threonine substitutions and amyloid diseases: butyrylcholinesterase as a case study. 2006 Aug 16

Alpha-synuclein (alpha-syn) is an amyloidogenic protein that plays a key role in the pathogenesis of Parkinson's disease (PD). The ability of alpha-syn oligomers to form ionic channels is postulated as a channelopathy mechanism in human brain. Here we identified a ganglioside-binding domain in alpha-syn (fragment 34-50), which includes the mutation site 46 linked to a familial form of PD (E46K). We show that this fragment is structurally related to the common glycosphingolipid-binding domain (GBD) shared by various microbial and amyloid proteins, including Alzheimer's beta-amyloid peptide. alpha-Syn GBD interacts with several glycosphingolipids but has a marked preference for GM3, a minor brain ganglioside whose expression increases with aging. The alpha-syn mutant E46K has a stronger affinity for GM3 than the wild-type protein, and the interaction is inhibited by 3'-sialyllactose (the glycone part of GM3). Alanine substitutions of Lys34 and Tyr39 in synthetic GBD peptides resulted in limited interaction with GM3, demonstrating the critical role of these residues in GM3 recognition. When incubated with reconstituted phosphatidylcholine bilayers, the E46K protein formed channels that are five times less conductive than those formed by wild-type alpha-syn, exhibit a higher selectivity for cations, and present an asymmetrical response to voltage and nonstop single-channel activity. This E46K-associated channelopathy was no longer observed when GM3 was present in phosphatidylcholine bilayers. This corrective effect was highly specific for GM3, since it was not obtained with the major brain ganglioside GM1 but was still detected in bilayer membranes containing both GM3 and GM1. Moreover, synthetic GBD peptides prevented the interaction of alpha-syn proteins with GM3, thus abolishing the regulatory effects of GM3 on alpha-syn-mediated channel formation. Overall, these data show that GM3 can specifically regulate alpha-syn-induced channel formation and raise the intriguing possibility that this minor brain ganglioside could play a key protective role in the pathogenesis of PD.
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PMID:Altered ion channel formation by the Parkinson's-disease-linked E46K mutant of alpha-synuclein is corrected by GM3 but not by GM1 gangliosides. 2011 52

Mitochondrial dysfunction has been linked to the pathogenesis of a large number of inherited diseases in humans, including Parkinson's disease, the second most common neurodegenerative disorder. The Parkinson's disease genes pink1 and parkin, which encode a mitochondrially targeted protein kinase, and an E3 ubiquitin ligase, respectively, participate in a key mitochondrial quality-control pathway that eliminates damaged mitochondria. In the current study, we established an in vivo PINK1/Parkin-induced photoreceptor neuron degeneration model in Drosophila with the aim of dissecting the PINK1/Parkin pathway in detail. Using LC-MS/MS analysis, we identified Serine 346 as the sole autophosphorylation site of Drosophila PINK1 and found that substitution of Serine 346 to Alanine completely abolished the PINK1 autophosphorylation. Disruption of either PINK1 or Parkin phosphorylation impaired the PINK1/Parkin pathway, and the degeneration phenotype of photoreceptor neurons was obviously alleviated. Phosphorylation of PINK1 is not only required for the PINK1-mediated mitochondrial recruitment of Parkin but also induces its kinase activity toward Parkin. In contrast, phosphorylation of Parkin by PINK1 is dispensable for its translocation but required for its activation. Moreover, substitution with autophosphorylation-deficient PINK1 failed to rescue pink1 null mutant phenotypes. Taken together, our findings suggest that autophosphorylation of PINK1 is essential for the mitochondrial translocation of Parkin and for subsequent phosphorylation and activation of Parkin.
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PMID:PINK1-dependent phosphorylation of PINK1 and Parkin is essential for mitochondrial quality control. 2790 79