Compositions and methods for dissolving protein aggregates
The present disclosure provides a polypeptide capable of dissolving protein aggregates. Also provided is a method of treating a neurodegeneration disease using the polypeptide.
1. A polypeptide comprising a hydrophilic segment and a hydrophobic segment,
wherein the hydrophilic segment comprises a sequence selected from the group consisting of:
TEPQEESEEEVEEPEER (SEQ ID NO: 15),
TDPQDDSDDDVDDPDDR (SEQ ID NO: 16),
TKPQKKSKKKVKKPKKR (SEQ ID NO: 17),
TRPQRRSRRRVRRPRRR (SEQ ID NO: 18),
ELDEESEDEVEEEQEDR (SEQ ID NO: 19),
KEEVDEDRDVDE (SEQ ID NO: 20), and
EKSEQDLE (SEQ ID NO: 21), or a sequence having at least 90% identity thereto,
wherein the hydrophobic segment comprises a sequence selected from the group consisting of:
TFYDQTVSNDL (SEQ ID NO: 22),
ANSAYYDAHPVTNGI (SEQ ID NO: 23),
PPQTAAREATSIPGFPAEGAIPLPV (SEQ ID NO: 24), and
EGEVAEEPNSRP (SEQ ID NO: 25), or a sequence having at least 90% identity thereto,
wherein the hydrophilic segment is at the N-terminus and the hydrophobic segment is at the C-terminus,
wherein the polypeptide has a length of 20-60 amino acid residues, and
wherein the polypeptide is capable of dissolving a protein aggregate.
2. The polypeptide of claim 1 , wherein the protein aggregate is fused in sarcoma (FUS) aggregate, TAR DNA-binding protein 43 (TDP43) aggregate, T-cell intracellular antigen-1 (TIA1) aggregate, chromosome 9 open reading frame 72 (C9orf72) aggregate or a combination thereof.
3. A method for dissolving a protein aggregate in a cell, the method comprising introducing to the cell the polypeptide of claim 1 , wherein the protein aggregate is FUS aggregate, and the cell is motor neuron.
4. A pharmaceutical composition comprising (1) the polypeptide of claim 1 , and (2) a pharmaceutically acceptable carrier.
5. A polynucleotide encoding a polypeptide comprising a hydrophilic segment and a hydrophobic segment, wherein the hydrophilic segment comprises a sequence selected from the group consisting of:
TEPQEESEEEVEEPEER (SEQ ID NO: 15),
TDPQDDSDDDVDDPDDR (SEQ ID NO: 16),
TKPQKKSKKKVKKPKKR (SEQ ID NO: 17),
TRPQRRSRRRVRRPRRR (SEQ ID NO: 18),
ELDEESEDEVEEEQEDR (SEQ ID NO: 19),
KEEVDEDRDVDE (SEQ ID NO: 20), and
EKSEQDLE (SEQ ID NO: 21), or a sequence having at least 90% identity thereto,
wherein the hydrophobic segment comprises a sequence selected from the group consisting of:
TFYDQTVSNDL (SEQ ID NO: 22),
ANSAYYDAHPVTNGI (SEQ ID NO: 23),
PPQTAAREATSIPGFPAEGAIPLPV (SEQ ID NO: 24), and
EGEVAEEPNSRP (SEQ ID NO: 25), or a sequence having at least 90% identity thereto,
wherein the hydrophilic segment is at the N-terminus and the hydrophobic segment is at the C-terminus,
wherein the polypeptide has a length of 20-60 amino acid residues, and
wherein the polypeptide is capable of dissolving a protein aggregate.
6. The polynucleotide of claim 5 , which is a DNA or an RNA.
7. A vector comprising the polynucleotide of claim 5 .
8. The vector of claim 7 , which is a virus vector.
9. The vector of claim 8 , which is an AAV vector.
10. A recombinant virus comprising the polynucleotide of claim 5 .
11. A pharmaceutical composition comprising (1) the polynucleotide of claim 5 and (2) a pharmaceutically acceptable carrier.
12. A method for treating a neurodegeneration disease in a subject in need thereof, the method comprising administering to the subject a therapeutic effective amount of the pharmaceutical composition of claim 11 , wherein the neurodegeneration disease is amyotrophic lateral sclerosis (ALS).
13. The method of claim 12 , wherein the pharmaceutical composition is administered to the central nervous system.
14. The method of claim 13 , wherein the pharmaceutical composition is administered via spinal cord injection, intrathecal injection, intracerebroventricular injection, intracerebral injection, or intra-hippocampal injection.
15. A polypeptide comprising a hydrophilic segment and a hydrophobic segment, wherein the polypeptide comprises a sequence selected from the group consisting of:
TEPQEESEEEVEEPEERQQTPEVVPDDSGTFYDQTVSNDLE (SEQ ID NO:1),
TDPQDDSDDDVDDPDDRQQTPDVVPDDSGTFYDQTVSNDLD (SEQ ID NO:2),
TKPQKKSKKKVKKPKKRQQTPKVVPDDSGTFYDQTVSNDLK (SEQ ID NO:3),
TRPQRRSRRRVRRPRRRQQTPRVVPDDSGTFYDQTVSNDLR (SEQ ID NO:4),
ELDEESEDEVEEEQEDRQPSPEPVQENANSAYYDAHPVTNGIE (SEQ ID NO: 8),
KEEVDEDRDVDESSPQDSPPSKASPAQDGRPPQTAAREATSIPGFPAEG AIPLPV (SEQ ID NO: 9), and
EGEVAEEPNSRPQEKSEQDLE (SEQ ID NO: 10),
or a sequence having at least 90% identity thereto,
wherein the polypeptide is capable of dissolving a protein aggregate.