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

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.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Medicine – Neuroscience

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2025

Author dc:creator

• Pontifex, Carly Sabine

Advisor dc:contributor.advisor

• Pfeffer, Gerald

Committee members dc:contributor.committeemember

• Whelan, Patrick
• Shutt, Timothy
• Corcoran, Jenn
• Milone
• Margherita
• Greenway
• Clive, Steven

• Multisystem Proteinopathy
• T-cell Intracellular Antigen1
• Sequestosome1
• Valosin-Containing Protein
• lysosome
• autophagosome
• autophagic flux
• single nucleus RNAseq
• myogenesis
• NF-ΚB
• autophagy
• digenic modifier

Statement 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.

Language dc:language.iso

en

DOI

https://dx.doi.org/10.11575/PRISM/48403

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/120797