Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenylate kinase 4 (AK4) is a unique member with no enzymatic activity in vitro in the adenylate kinase (AK) family although it shares high sequence homology with other AKs. It remains unclear what physiological function AK4 might play or why it is enzymatically inactive. In this study, we showed increased AK4 protein levels in cultured cells exposed to hypoxia and in an animal model of the neurodegenerative disease amyotrophic lateral sclerosis. We also showed that short hairpin RNA (shRNA)-mediated knockdown of AK4 in HEK293 cells with high levels of endogenous AK4 resulted in reduced cell proliferation and increased cell death. Furthermore, we found that AK4 over-expression in the neuronal cell line SH-SY5Y with low endogenous levels of AK4 protected cells from H(2)O(2) induced cell death. Proteomic studies revealed that the mitochondrial ADP/ATP translocases (ANTs) interacted with AK4 and higher amount of ANT was co-precipitated with AK4 when cells were exposed to H(2)O(2) treatment. In addition, structural analysis revealed that, while AK4 retains the capability of binding nucleotides, AK4 has a glutamine residue instead of a key arginine residue in the active site well conserved in other AKs. Mutation of the glutamine residue to arginine (Q159R) restored the adenylate kinase activity with GTP as substrate. Collectively, these results indicate that the enzymatically inactive AK4 is a stress responsive protein critical to cell survival and proliferation. It is likely that the interaction with the mitochondrial inner membrane protein ANT is important for AK4 to exert the protective benefits to cells under stress.
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PMID:Enzymatically inactive adenylate kinase 4 interacts with mitochondrial ADP/ATP translocase. 1913 Aug 95

More than 140 mutations in the SOD1 gene cause aggregation of the affected protein in familial forms of amyotrophic lateral sclerosis (fALS) which is a fatal progressive neurodegenerative disorder selectively affecting motor neurons. The causes of motor neuron death in ALS are poorly understood in general, but for fALS, aberrant oligomerization of SOD1 mutant proteins has been strongly concerned. Increasing evidences indicate that the interaction of amyloid aggregates with membranes is critical in the onset and progression of amyloid diseases. In spite of gathering reports describing mechanisms of membrane permeabilization by aggregates in model membranes, studies focused at characterizing the events occurring in biological membranes are exceptional. To gain insight into possible mechanisms of cytotoxicity at the membrane level, we describe interaction of the fibrillation products of the wild type (WT) and two mutants (E100K, D125H) of SOD1 obtained under destabilizing conditions with mitochondrial membranes. Release of mitochondrial enzymes, malate dehydrogenase (MDH) and adenylate kinase (AK), upon exposure to SOD1 aggregates demonstrates that these aggregates could affect membrane integrity. This effect correlates with the surface hydrophobicity of oligomers and their tendency toward amyloid formation, with the most toxic oligomers having high hydrophobicity and increased amount of amyloid formation.
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PMID:Mitochondrial membrane disruption by aggregation products of ALS-causing superoxide dismutase-1 mutants. 2560 Sep 87