Parallels and Divergences in Multisystem Proteinopathy Genes: Stress Granules, Autophagy, and Myogenic Deficits

Pontifex, Carly Sabine

Parallels and Divergences in Multisystem Proteinopathy Genes: Stress Granules, Autophagy, and Myogenic Deficits

dc.contributor.advisor	Pfeffer, Gerald
dc.contributor.author	Pontifex, Carly Sabine
dc.contributor.committeemember	Whelan, Patrick
dc.contributor.committeemember	Shutt, Timothy
dc.contributor.committeemember	Corcoran, Jenn
dc.contributor.committeemember	Milone
dc.contributor.committeemember	Margherita
dc.contributor.committeemember	Greenway
dc.contributor.committeemember	Clive, Steven
dc.date	2025-05
dc.date.accessioned	2025-02-19T17:26:29Z
dc.date.available	2025-02-19T17:26:29Z
dc.date.issued	2025-01-31
dc.description.abstract	Multisystem Proteinopathy (MSP) is a disease that causes some combination of inclusion body myopathy with rimmed vacuoles, Paget’s disease of bone, and ALS/FTD. Several different genes give rise to the unique phenotypic expression of MSP. Given the variety of genes that cause MSP and the specificity of the phenotype and tissue involvement, we asked; what are the unifying pathogenic features of MSP? To address this, we examined three areas of interest: stress granules, autophagy, and myogenesis. The currently identified roster of MSP genes have several structural and functional commonalities which fall into two categories: LC3B-intracting domain containing autophagy adaptors (SQSTM1, VCP, OPTN) and prion-like domain containing stress granule proteins (HNRNPA2B1, HNRNPA1, MATR3, TIA1). Previous studies identified that a non-pathogenic variant of the non-classical MSP protein, TIA1 N357S , can act as a phenotype modifier with SQSTM1P392L leading to distal muscle weakness rather than proximal muscle weakness seen with monogenic SQSTM1 mutations. Here we show that the same TIA1 variant is able to act as a modifier with VCP R159H to produce the same distal weakness. We established three major findings: 1) The non-classical MSP gene TIA1 N357S can modify the myopathy phenotype of both VCP and SQSTM1 to produce distal rather than proximal muscle weakness at the onset of disease, and that TIA1b expression drives the increase of TIA1 expression in diseased muscle and also fails to colocalize with SQSTM1—implying that upregulation of TIA1b is important for muscle stress response and also that TIA1b stress granules have reduced clearance by autophagy. 2) VCP and SQSTM1 both exhibit lysosome accumulation, which may be an emergent feature of inclusion body myopathies. 3) Impaired myogenesis via resistance to the master regulator of myogenesis MyoD, is a feature of MSP.
dc.identifier.citation	Pontifex, C. S. (2025). Parallels and divergences in multisystem proteinopathy genes: stress granules, autophagy, and myogenic deficits (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.uri	https://hdl.handle.net/1880/120797
dc.language.iso	en
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	Multisystem Proteinopathy
dc.subject	T-cell Intracellular Antigen1
dc.subject	Sequestosome1
dc.subject	Valosin-Containing Protein
dc.subject	lysosome
dc.subject	autophagosome
dc.subject	autophagic flux
dc.subject	single nucleus RNAseq
dc.subject	myogenesis
dc.subject	NF-ΚB
dc.subject	autophagy
dc.subject	digenic modifier
dc.subject.classification	Neuroscience
dc.title	Parallels and Divergences in Multisystem Proteinopathy Genes: Stress Granules, Autophagy, and Myogenic Deficits
dc.type	doctoral thesis
thesis.degree.discipline	Medicine – Neuroscience
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.