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Establishing model systems to study mechanisms of cell specificity in Autosomal Dominant Leukodystrophy

Oranburg, Talia DeFrancesco (2023) Establishing model systems to study mechanisms of cell specificity in Autosomal Dominant Leukodystrophy. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Autosomal Dominant Leukodystrophy (ADLD) is an adult-onset fatal demyelinating disease caused by overexpression of the nuclear lamina protein, lamin B1. Patients exhibit varying mutations involving the gene that encodes this protein, LMNB1, including various sized duplications and upstream deletions. A mouse model in which overexpression is driven specifically in oligodendrocytes (OLs) shows a similar phenotype to ADLD patients including adult-age onset and vacuolar degeneration of the white matter. We hypothesize that the structural mutations (duplications and upstream deletions) perturb regulatory elements that regulate the expression of LMNB1 in a cell specific manner that, in turn, lead to the overexpression and disease phenotype. Since ADLD is a demyelinating disease, we believe that the cell type most relevant to disease is the myelinating cell of the central nervous system, the OL.
I have shown that OLs are not uniquely susceptible to the deleterious effects of LMNB1 overexpression by analyzing peripheral myelination, in our mouse model of ADLD. In these mice in which LMNB1 overexpression is targeted to both OLs and Schwann cells, we see myelin deficits in peripheral nerves as well. To address the cell specificity of LMNB1 overexpression, I have shown that iPSCs derived from patients with various classes of mutations involving the lamin B1 gene can be differentiated into the ADLD-relevant CNS cell types. Interrogating lamin B1 overexpression identifies cell type specific alterations specific to each mutation class. I have also shown that CRISPR-Cas9 can be used to correct the duplications in iPSCs and restore LMNB1 expression to normal levels.
As a fatal disease with no cure, ADLD presents an unmet public health need. Since the disease affects tissues unavailable for study during life, an in vitro paradigm is crucial to help improve a mechanistic understanding of ADLD. Combined with CRISPR-Cas9, this system may further elucidate potential therapeutic targets for these patients. Although ADLD is a rare disease, there are many demyelinating disorders, such as multiple sclerosis (MS) which are much more prevalent and present a tremendous public health burden. The work described here informs options for understanding and treating these diseases as well.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Oranburg, Talia DeFrancescotoranburg@gmail.comald2400000-0001-5925-5217
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorPadiath,
Committee MemberRoman,
Committee MemberKemaladewi,
Committee MemberDonnelly,
Committee MemberFossati,
Date: 9 May 2023
Date Type: Publication
Defense Date: 2 February 2023
Approval Date: 9 May 2023
Submission Date: 19 April 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 110
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: LMNB1, lamin B1, CNS, oligodendrocytes, CRISPR, white matter
Date Deposited: 10 May 2023 01:53
Last Modified: 10 May 2023 01:53


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