Inhibition of α-ketoglutarate-and pyruvate dehydrogenase complexes in E. coli by a glutathione S-transferase containing a pathological length poly-Q domain: A possible role of energy deficit in neurological diseases associated with poly-Q expansions?

Abstract

At least seven adult-onset neurodegenerative diseases, including Huntington's disease (HD),

Novel Metabolic Abnormalities in the Tricarboxylic Acid Cycle in Peripheral Cells From Huntington’s Disease Patients

“…One preliminary study in the putamen of brains from controls and HD patients suggests that KGDHC activity is reduced [ 16 ]. E. coli with 62 CAG repeats exhibit significantly impaired KGDHC activity compared to controls [ 38 , 39 ]. DLST (dihydrolipoyl succinyl transferase) is one of the three subunits of the KGDHC.…”

Pathogenesis of Inclusion Bodies in (CAG)n/Qn‐Expansion Diseases with Special Reference to the Role of Tissue Transglutaminase and to Selective Vulnerability

“…Several authors have used transfected Escherichia coli to study the effects of Q n ‐expanded proteins on the intracellular aggregates that form in these bacteria. E. coli does not possess transglutaminase activity (Cooper et al, 1998). Indeed, transfection of this bacterium with a transglutaminase from a different bacterium results in inhibition of cell growth and lysis (Takehana et al, 1994).…”

“…Scherzinger et al (1997) reported that a glutathione S ‐transferase (GST)‐fusion protein containing an expanded Q n domain forms amyloidlike protein aggregates (indicative of β‐pleated sheet formation) in E. coli . GSTQ n constructs containing small Q n domains (n = 10‐35) are not toxic to E. coli , whereas GSTQ n ‐fusion proteins containing longer repeats are toxic (Onodera et al, 1996 ; Cooper et al, 1998). Aggregate formation, however, occurs much more rapidly in transfected E. coli than in the (CAG) n /Q n ‐expansion diseases where cellular aggregate formation may take many years.…”