Lashuel, Hilal

Research Interests

Research Projects:

Research Projects in the laboratory of Molecular Neurobiology and Functional Neuroproteomics cover the following topics:

Elucidating the structural basis of amyloid-associated toxicity in neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease.
Understanding the role of quaternary structure in protein function and disease.
Exploiting amyloid fibril formation for constructing polypeptide materials with potential applications in biotechnology and medicine.

Elucidating the structural basis of amyloid-associated toxicity in neurodegenerative diseases.

Research efforts in our laboratory focus on understanding the role of protein aggregation, more specifically amyloid fibril formation, in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington disease. In particular, we are working on defining the biochemical mechanism of amyloid fibril formation of two amyloidogenic proteins, α -synuclein and amyloid-β (Aβ), and how they contribute to each of their respective diseases, Parkinson's and Alzheimer's diseases. Using a multifaceted approaches that employ tools from chemistry, biophysics, structural biology, and molecular and cell biology, our group is working to elucidate the structural basis of amyloid toxicity in neurodegenerative diseases. A detailed understanding of the mechanism of amyloid fibril formation and its relation to disease pathology should contribute to our understanding of the mechanism of pathogenesis and the identification of therapeutic targets for treating and/or preventing these devastating diseases.

Exploiting amyloid fibril formation for constructing biomaterials with applications in nanotechnology and medicine.

Deciphering the mechanism(s) of β-sheet mediated self-assembly is essential for understanding amyloid fibril formation and for the fabrication of polypeptide materials. The self-assembly of peptides and proteins into noncovalent β-sheet rich quaternary structures, including fibrils, has attracted the attention of numerous laboratories owing to their association with neurodegenerative disease and their interesting structural properties. In both amyloid and prion diseases a normally soluble protein or proteolytic fragment undergoes a conformational change either prior to, or coincident with, its self-assembly into β-sheet rich fibrils, implicated as the causative agent in numerous neurodegenerative diseases by genetic linkage.

The ability of small polypeptides and peptidomimetics to self-assemble into highly ordered polymorphic β-sheet fibrillar structures is based on molecular recognition principles. The intermolecular forces can be increased or attenuated to change the distribution of quaternary structures afforded by manipulating the structure of the polypeptide or by changing the solution conditions. The potential to vary the hydrophobicity, the length of the peptide strands, the nature of side chains and the strand termini by straightforward solid-phase peptide synthesis methods should prove very powerful for the preparation of biomaterials and for further understanding the mechanism(s) of self-assembly. We plan to use our understanding of the mechanism of amyloid fibril formation to control the self-assembly of amyloid forming peptides to fabricate biomaterials with potential applications in nanotechnology and medicine.

Key Publications

Lansbury PT* and Lashuel HA*. "A century old debate on protein aggregation and neurodegeneration enters the clinic". Nature, 2006, 443, 774-779.

Lashuel HA* and Harald Hirling. "Rescuing defective vesicular trafficking protects against alpha-synuclein toxicity in cellular and animal models of Parkinson's disease. ACS Chemical Biology, 2006, 1(7), 1, 420-424.

Lashuel HA* and Lansbury PT*. " Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?" Quarterly Review of Biophysics. 2006, 39 (2), 1-35.

Mimna R., Camus M-S., Schmid A., Tuchscherer G., Lashuel HA*., Mutter M*. "Switch Peptides: Disruption of amyloid fibrils through controlled induction of beta-sheet to alpha-helix transformation". Angew Chem Int Ed Engl, 2006, In press.

Lashuel HA*. "Membrane Permeabilization: A Common Mechanism in Protein Misfolding Diseases: If it look like a pore and acts like a pore, is it a pathogenic pore?". Sci Aging Knowledge Environ. 2005 (38), pe28 (2005). (link)

Lashuel HA*, Aljabari B, Sigurdsson EM, Metz CN, Leng L, Callaway DJ, and Bucala R. "Amyloid Fibril Formation by Macrophage Migration Inhibitory Factor (MIF)", Biochem. Biophys. Res. Comm, 2005, 338(2):973-80.

Morikawa M, Fryer JD, Sullivan PM, Christopher EA, Wahrle SE, DeMattos, O'Dell MA, Fagan AM, Lashuel HA, Walz T, Asai K, and Holtzman D. "Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-¦Â " Neurobiology of Disease, 2005, 19 (1-20), 66-76.

Cox DL, Lashuel HA, Lee KY, and Singh R.R.P. "The material science of protein. Aggregation". Material Research Society Bulletin. 2005, 30, 6, 452-459.

Basha R, Murali M, Siddiqi HK, Ghosal K, Siddiqi OK, Lashuel HA, Zawia NH. "Exposure to lead (Pb) promotes b-amyloid aggregation but does not affect the proteolytic processing of the Amyloid Precursor Protein (APP)", FASEB J, 2005, 19(14):2083-4.

Wang, L., Lashuel, HA, and Col¨®n, W. "From Hexamer to Amyloid: Marginal stability of apolipoprotein SAA2.2 leads to in vitro fibril formation at physiological temperature",The Journal of Protein Folding Disorders, 2005, 12, 139-148.

Nakagawa T, Futai K, Lashuel HA, Lo I, Okamoto K, Hayashi Y, Walz T, and Sheng M. "EM Structure, Protein Dynamics and Synaptic Function of SAP97, and AMPA Receptor Scaffold Protein". Neuron, 2004, 28;44(3):453-67.

Lashuel HA, Petre B, Wall, Simon M, Nowak RJ, Walz T, Lansbury PT. "y-synuclein, Especially the Parkinson's Disease Associated Mutants, Form Pore-Like Annular and Tubular Protofibrils-,Mol. Biol. 2002, 322, 5, 1089-1102

Laboratory of Molecular Neurobiology and Functional Neuroproteomics

Research Interests

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Key Publications