Abstract
While the roles of intrinsically disordered protein domains in driving interprotein interactions are increasingly well-appreciated, the mechanism of toxicity of disease-causing disordered proteins remains poorly understood. A prime example is Alzheimer's disease (AD) associated amyloid beta (Aβ). Aβ oligomers are highly toxic partially structured peptide assemblies with a distinct ordered region (residues 10-40) and a shorter disordered region (residues 1-9). Here, we investigate the role of this disordered domain and its relation to the ordered domain in the manifestation of toxicity through a set of Aβ fragments and stereoisomers designed for this purpose. We measure their effects on lipid membranes and cultured neurons, probing their toxicity, intracellular distributions, and specific molecular interactions using the techniques of confocal imaging, lattice light sheet imaging, fluorescence lifetime imaging, and fluorescence correlation spectroscopy. Remarkably, we find that neither part - Aβ10-40 or Aβ1-9, is toxic by itself. The ordered part (Aβ10-40) is the major determinant of how Aβ attaches to lipid bilayers, enters neuronal cells, and localizes primarily in the late endosomal compartments. However, once Aβ enters the cell, it is the disordered part (only when it is connected to the rest of the peptide) that has a strong and stereospecific interaction with an unknown cellular component, as demonstrated by distinct changes in the fluorescence lifetime of a fluorophore attached to the N-terminal. This interaction appears to commit Aβ to the toxic pathway. Our findings correlate well with Aβ sites of familial AD mutations, a significant fraction of which cluster in the disordered region. We conclude that, while the ordered region dictates attachment and cellular entry, the key to toxicity lies in the ordered part presenting the disordered part for a specific cellular interaction.
| Original language | English |
|---|---|
| Pages (from-to) | 2498-2509 |
| Number of pages | 12 |
| Journal | ACS Chemical Neuroscience |
| Volume | 10 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 15 May 2019 |
| Externally published | Yes |
Keywords
- Alzheimer's disease (AD)
- Amyloid beta fragment
- Amyloid beta interactions
- amyloid enantiomer
- amyloid-membrane interaction
- Intracellular amyloid beta
Cite this
}
Ordered and Disordered Segments of Amyloid-β Drive Sequential Steps of the Toxic Pathway. / Maity, Barun Kumar; Das, Anand Kant; Dey, Simli; Moorthi, Ullhas Kaarthi; Kaur, Amandeep; Dey, Arpan; Surendran, Dayana; Pandit, Rucha; Kallianpur, Mamata; Chandra, Bappaditya; Chandrakesan, Muralidharan; Arumugam, Senthil; Maiti, Sudipta.
In: ACS Chemical Neuroscience, Vol. 10, No. 5, 15.05.2019, p. 2498-2509.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Ordered and Disordered Segments of Amyloid-β Drive Sequential Steps of the Toxic Pathway
AU - Maity, Barun Kumar
AU - Das, Anand Kant
AU - Dey, Simli
AU - Moorthi, Ullhas Kaarthi
AU - Kaur, Amandeep
AU - Dey, Arpan
AU - Surendran, Dayana
AU - Pandit, Rucha
AU - Kallianpur, Mamata
AU - Chandra, Bappaditya
AU - Chandrakesan, Muralidharan
AU - Arumugam, Senthil
AU - Maiti, Sudipta
PY - 2019/5/15
Y1 - 2019/5/15
N2 - While the roles of intrinsically disordered protein domains in driving interprotein interactions are increasingly well-appreciated, the mechanism of toxicity of disease-causing disordered proteins remains poorly understood. A prime example is Alzheimer's disease (AD) associated amyloid beta (Aβ). Aβ oligomers are highly toxic partially structured peptide assemblies with a distinct ordered region (residues 10-40) and a shorter disordered region (residues 1-9). Here, we investigate the role of this disordered domain and its relation to the ordered domain in the manifestation of toxicity through a set of Aβ fragments and stereoisomers designed for this purpose. We measure their effects on lipid membranes and cultured neurons, probing their toxicity, intracellular distributions, and specific molecular interactions using the techniques of confocal imaging, lattice light sheet imaging, fluorescence lifetime imaging, and fluorescence correlation spectroscopy. Remarkably, we find that neither part - Aβ10-40 or Aβ1-9, is toxic by itself. The ordered part (Aβ10-40) is the major determinant of how Aβ attaches to lipid bilayers, enters neuronal cells, and localizes primarily in the late endosomal compartments. However, once Aβ enters the cell, it is the disordered part (only when it is connected to the rest of the peptide) that has a strong and stereospecific interaction with an unknown cellular component, as demonstrated by distinct changes in the fluorescence lifetime of a fluorophore attached to the N-terminal. This interaction appears to commit Aβ to the toxic pathway. Our findings correlate well with Aβ sites of familial AD mutations, a significant fraction of which cluster in the disordered region. We conclude that, while the ordered region dictates attachment and cellular entry, the key to toxicity lies in the ordered part presenting the disordered part for a specific cellular interaction.
AB - While the roles of intrinsically disordered protein domains in driving interprotein interactions are increasingly well-appreciated, the mechanism of toxicity of disease-causing disordered proteins remains poorly understood. A prime example is Alzheimer's disease (AD) associated amyloid beta (Aβ). Aβ oligomers are highly toxic partially structured peptide assemblies with a distinct ordered region (residues 10-40) and a shorter disordered region (residues 1-9). Here, we investigate the role of this disordered domain and its relation to the ordered domain in the manifestation of toxicity through a set of Aβ fragments and stereoisomers designed for this purpose. We measure their effects on lipid membranes and cultured neurons, probing their toxicity, intracellular distributions, and specific molecular interactions using the techniques of confocal imaging, lattice light sheet imaging, fluorescence lifetime imaging, and fluorescence correlation spectroscopy. Remarkably, we find that neither part - Aβ10-40 or Aβ1-9, is toxic by itself. The ordered part (Aβ10-40) is the major determinant of how Aβ attaches to lipid bilayers, enters neuronal cells, and localizes primarily in the late endosomal compartments. However, once Aβ enters the cell, it is the disordered part (only when it is connected to the rest of the peptide) that has a strong and stereospecific interaction with an unknown cellular component, as demonstrated by distinct changes in the fluorescence lifetime of a fluorophore attached to the N-terminal. This interaction appears to commit Aβ to the toxic pathway. Our findings correlate well with Aβ sites of familial AD mutations, a significant fraction of which cluster in the disordered region. We conclude that, while the ordered region dictates attachment and cellular entry, the key to toxicity lies in the ordered part presenting the disordered part for a specific cellular interaction.
KW - Alzheimer's disease (AD)
KW - Amyloid beta fragment
KW - Amyloid beta interactions
KW - amyloid enantiomer
KW - amyloid-membrane interaction
KW - Intracellular amyloid beta
UR - http://www.scopus.com/inward/record.url?scp=85062542412&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.9b00015
DO - 10.1021/acschemneuro.9b00015
M3 - Article
C2 - 30763064
AN - SCOPUS:85062542412
VL - 10
SP - 2498
EP - 2509
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 5
ER -