Increased aggregation of polyleucine compared with that of polyglutamine in dentatorubral-pallidoluysian atrophy protein.
Polyglutamine (polyQ) diseases result from expansion of CAG trinucleotide repeats in their responsible genes. Although gene products with polyQ expansions undergo conformational changes to aggregate in neurons, the relationship between inclusions and neurotoxicity remains unclear. Dentatorubral-pallidoluysian atrophy (DRPLA) is a polyQ disease, and DRPLA protein, also known as atrophin-1 (ATN1), carries an expanded polyQ tract. To investigate how an expanded polyQ tract influences ATN1 aggregation and localization, we compared the aggregation of ATN1 with a polyQ tract to that of ATN1 with a polyleucine (polyL) tract. In COS-7 cells, polyL-ATN1 triggered more aggregation than polyQ-ATN1 of similar repeat sizes. Immunocytochemical and biochemical studies revealed that replacement of the polyQ tract with polyL alters ATN1 localization, leading to retention of polyL-ATN1 in the cytoplasm. Despite this change in localization, polyL-ATN1 and polyQ-ATN1 demonstrate comparable repeat length dependent toxicity. These results suggest that expanded polyQ repeats in ATN1 may contribute to neurodegeneration via alterations in both protein aggregation and intracellular localization.
Laboratory of Research Resources, Research Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan.
Yasuyo
Y
Suzuki
Chenghua
C
Jin
Ikuru
I
Yazawa
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D050505:Mutant Proteins / Q000009:adverse effects* / Q000235:genetics; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000633:toxicity*; D018911:Trinucleotide Repeats
D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C095278:atrophin-1; C027819:polyleucine; C097188:polyglutamine
ATN1; Atrophin-1; CNS; DRPLA; Dentatorubral-pallidoluysian atrophy; HD; Huntington's disease; N,N,N′,N′-tetrakis (2-pyridylmethyl) ethylenediamine; Neurodegeneration; Polyglutamine; Polyleucine; SCA; TPEN; Z-VAD-FMK; atrophin-1; benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone.; central nervous system; dentatorubral-pallidoluysian atrophy; polyL; polyQ; polyglutamine; polyleucine; spinocerebellar ataxia