Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Huntington’s Disease Studies at the Interface of Chemistry, Physics, and Biology

Drombosky, Kenneth (2016) Huntington’s Disease Studies at the Interface of Chemistry, Physics, and Biology. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (2MB)


Huntington’s disease (HD) is a uniformly fatal genetic disease causing progressive degeneration of the central nervous system in approximately 250,000 people worldwide. Unlike other neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, HD is explicitly caused by a single genetic defect – a CAG codon expansion in the huntingtin gene, which codes for polyglutamine (polyQ) in the protein huntingtin (htt). People carrying 40 or more CAG/glutamine repeats will develop HD by early adulthood, while those with 36 or less are unaffected. Despite this discovery over two decades ago, there are still no treatments to cure, prevent, or delay the underlying progression of HD.
The physical state of the huntingtin “exon1” fragment responsible for triggering HD pathology (amyloid aggregates, non-β oligomers, or monomers) is a controversial roadblock that limits therapeutic discovery. Previous attempts to determine the toxic species have recently been identified as flawed or inconclusive. Herein, we describe mutated htt-exon1 analogs containing only 22-24 glutamine residues that deliver atypical aggregation: a “hyper-amyloid” analog that – despite its short glutamine repeat lengths – aggregates into amyloid fibrils comparable to pathogenic huntingtin, and “hypo-amyloid” analogs whose aggregation stops at the non-β oligomer stage. Hyper-amyloid htt-exon1 produces inclusions, cytotoxicity in rat neurons, and decreased lifespans with movement deficits in flies. Neurons and flies expressing hypo-amyloid htt-exon1 alone have no detectible HD phenotype. Our data strongly supports a toxic amyloid hypothesis, and we find no evidence of a toxic non-β oligomer.
Furthermore, the non-toxic hypo-amyloid analogs are also able to inhibit amyloid formation of pathogenic repeat length htt-exon1. Co-expression of hypo-amyloid htt-exon1 with pathogenic htt-exon1 reduces aggregation in vitro, inhibits toxicity in neuron cultures, and rescues behavioral and lifespan HD phenotypes in flies. These exciting results offer novel, rationally designed approaches to HD therapeutics.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Drombosky, Kennethdromboskyk@gmail.comKWD70000-0002-3602-0789
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorWetzel, Ronrwetzel@pitt.eduRWETZEL
Committee ChairPalladino, Michael Jmjp44@pitt.eduMJP44
Committee MemberJacob, Tijatcj11@pitt.eduTCJ11
Committee MemberThibodeau, Patrick H.thibodea@pitt.eduTHIBODEA
Committee MemberDeFranco, Donalddod1@pitt.eduDOD1
Date: 20 May 2016
Date Type: Publication
Defense Date: 14 March 2016
Approval Date: 20 May 2016
Submission Date: 26 April 2016
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 177
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Huntington, Huntingtin, Amyloid, Aggregation, Drosophila, Primary Neuron
Date Deposited: 20 May 2016 15:13
Last Modified: 15 Nov 2016 14:33


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item