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)

TDP-43 and FUS are DNA/RNA binding proteins associated with neuronal inclusions in amyotrophic lateral sclerosis (ALS) patients. Other neurodegenerative diseases are also characterized by neuronal protein aggregates, e.g. Huntington's disease, associated with polyglutamine (polyQ) expansions in the protein huntingtin. Here we discuss our recent paper establishing similarities between aggregates of TDP-43 that have short glutamine and asparagine (Q/N)-rich modules and are soluble in detergents, with those of polyQ and PIN4C that have large Q/N-rich domains and are detergent-insoluble. We also present new, similar data for FUS. Together, we show that like overexpression of polyQ or PIN4C, overexpression of FUS or TDP-43 causes inhibition of the ubiquitin proteasome system (UPS) and toxicity, both of which are mitigated by overexpression of the Hsp40 chaperone Sis1. Also, in all cases toxicity is enhanced by the [PIN+] prion. In addition, we show that the Sis1 mammalian homolog DNAJBI reduces toxicity arising from overexpressed FUS and TDP-43 respectively in human embryonic kidney cells and primary rodent neurons. The common properties of these proteins suggest that heterologous aggregates may enhance the toxicity of a variety of disease-related aggregating proteins, and further that chaperones and the UPS may be key therapeutic targets for diseases characterized by protein inclusions.
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PMID:Overexpression of a conserved HSP40 chaperone reduces toxicity of several neurodegenerative disease proteins. 2930 90

Interactions amongst different amyloid proteins have been proposed as a probable mechanism of aggregation and thus an important risk factor for the onset as well as progression of various neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis. Evidences suggest that transthyretin (TTR), a plasma protein associated with transthyretin amyloidosis or familial polyneuropathy (FAP) interacts with heterologous amyloid proteins including amyloid beta and islet amyloid polypeptide. In addition, recent clinical studies have revealed the presence of systemic polyneuropathy associated with FAP mutations in patients with spinocerebral ataxia, amyotrophic lateral sclerosis, and new familial systematic prion disease. Hence, it is important to investigate the interactions amongst different amyloid proteins to gain better insight into the pathology of amyloid disorders. Yeast has been an excellent model system to study interaction/ cross-seeding between heterologous amyloid proteins, more because of presence of endogenous yeast prions. Here, we examined interactions of non-glutamine (non-Q)-rich transthyretin, with glutamine (Q)-rich yeast prion protein Sup35. We established aggregation of an engineered double (F87M/L110M) mutant M-TTR-GFP in yeast. This mutant is monomeric and readily formed aggregates compared to WT-TTR-GFP in yeast at acidic pH. Interestingly, aggregation of M-TTR-GFP was significantly enhanced in presence of [PSI+], an endogenous prion form of Sup35. Different variants of [PSI+] seeded M-TTR-GFP with different efficiencies and curing of [PSI+] (losing the prion form) in these strains reduced aggregation. Moreover, overexpression of prion domain of Sup35 fused to RFP (NM-RFP) also increased M-TTR-GFP aggregation. M-TTR-GFP and NM-RFP aggregates co-localized in perivacuolar and juxtranuclear region. Sup35 protein was even immunocaptured in M-TTR-GFP aggregates. However, M-TTR-GFP overexpression did not induce Sup35 aggregation. Thus, it appears to be a unidirectional interaction between these two amyloid proteins. However, no affect on M-TTR-GFP aggregation was observed due to another yeast prion, [PIN+]. Our findings thus show the molecular interaction of transthyretin with yeast prion and support that sequence similarity is not the prime requirement for heterologous amyloid interactions.
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PMID:Q-Rich Yeast Prion [PSI+] Accelerates Aggregation of Transthyretin, a Non-Q-Rich Human Protein. 2959 96