Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases.
Misfolded proteins accumulate in many neurodegenerative diseases, including huntingtin in Huntington's disease and alpha-synuclein in Parkinson's disease. The disease-causing proteins can take various conformations and are prone to aggregate and form larger cytoplasmic or nuclear inclusions. One approach to the development of therapeutic intervention for these diseases has been to identify chemical compounds that reduce the size or number of inclusions. We have, however, identified a compound that promotes inclusion formation in cellular models of both Huntington's disease and Parkinson's disease. Of particular interest, this compound prevents huntingtin-mediated proteasome dysfunction and reduces alpha-synuclein-mediated toxicity. These results demonstrate that compounds that increase inclusion formation may actually lessen cellular pathology in both Huntington's and Parkinson's diseases, suggesting a therapeutic approach for neurodegenerative diseases caused by protein misfolding.
Center for Cancer Research, Massachusetts Institute of Technology, Room E18-505, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Ruth A
RA
Bodner
Tiago Fleming
TF
Outeiro
Stephen
S
Altmann
Michele M
MM
Maxwell
Stephanie H
SH
Cho
Bradley T
BT
Hyman
Pamela J
PJ
McLean
Anne B
AB
Young
David E
DE
Housman
Aleksey G
AG
Kazantsev
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004274:DNA, Recombinant / Q000235:genetics; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D002479:Inclusion Bodies / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D011804:Quinolines / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D051844:alpha-Synuclein / Q000633:toxicity
D004274:DNA, Recombinant; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D011804:Quinolines; D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D046988:Proteasome Endopeptidase Complex