Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patient 1 was a 39-year-old man; patient 2, a 42-year-old woman; patient 3, a 78-year-old man. Leading symptoms were chronic asymmetrical weakness in all three cases, which started in a distal portion of the upper extremities. Muscle atrophy was often less prominent than would be expected from the power of the muscle. Fasciculations were observed in two patients and the initial symptom of patient 2 was painful cramp of the right thumb. Patient 1 initially had mild transient dysesthesia of the right fingers. The other two patients had no sensory symptoms or signs. General laboratory tests revealed no particular abnormalities except that patient 3 had mild diabetes mellitus, although the type of neuropathy in patient 3 was quite different from diabetic neuropathy. Total protein concentrations in the cerebrospinal fluid were 34, 32 and 43 mg/dl in three patients, respectively (normally, less than 40 mg/dl). Motor nerve conduction studies revealed conduction block in more than one nerve in every case. Conduction velocities were generally normal in those segments of nerve where conduction block was not detected. Serum anti-ganglioside antibodies were investigated by Enzyme-linked immunosorbent assay (ELISA). Glycolipids used as the antigen include GM1, GM2, GM3, GD1b, GD3, GT1b, GQ1b, GA1 and galactocerebroside. Strong IgM antibody activity against GM1, GD1b and GA1 was noted in patient 1. Weaker but significant IgM antibody activities against GM1 and GA1 were detected in patient 2 and 3. Thin-layer chromatography immunostaining also confirmed these results. Muscle biopsy in patient 1 revealed a lot of target fibers and profuse polyglucosan bodies in the axons of intramuscular nerves.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Motor-dominant neuropathy with multifocal conduction block]. 208 27

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