Gerold Schmitt-Ulms

Dr. Gerold Schmitt-Ulms trained in the laboratory of Dr. Stanley Prusiner at the University of California San Francisco before joining the Tanz Centre for Research in Neurodegenerative Diseases (Tanz CRND).

He is a Graduate Faculty Member of the Collaborative Program in Neuroscience (CPIN) and the Department of Laboratory Medicine and Pathobiology (LMP), University of Toronto.

Research Synopsis

Our work focuses on Alzheimer’s disease, prion disorders and related dementias.

We study how the function of key proteins is perturbed in these diseases.

Our main interests are:

1. Molecular events that lead to toxic Aβ assemblies,
2. Signaling of Aβ to Tau, and
3. How disease-associated conformers of Tau or the prion protein cause cells to die.

The objectives are to derive early diagnostics and mechanism-based disease interventions.

In-depth interrogation of protein-protein networks of key dementia proteins

Insights into the genetic causes of neurodegenerative diseases have grown rapidly, with dozens of new disease genes identified.

A lack of information on how the proteins coded by these new disease genes drive neurodegeneration stands in the way of progress today.

Proteins do not act in isolation but partner with others around them to fulfill their many functions. This group studies how disease proteins cause cellular toxicity with a view to identify rationale disease intervention strategies.

The study of molecular interactions of neurodegenerative disease proteins often begins with the building of novel cell and animal models. To this end, we routinely apply complex gene editing methods. We are also continuously advancing methods that can uncover physical and genetic interactions amongst proteins.

Highlights of our protein-protein interaction work in the past ten years were:

• interactome analyses of the Alzheimer’s disease-linked amyloid precursor protein (APP)
• γ-secretase complexes
• the abeta amyloid peptide (Aβ) and the tau protein
• the Creutzfeldt-Jakob Disease (CJD)-linked prion protein (PrP)
• the Parkinson’s disease-linked protein DJ-1
• the Amyotrophic Lateral Sclerosis (ALS)-linked protein fused in sarcoma (Fus).

For Aβ, Tau, and PrP our quantitative interactome data were the first to become available, for other bait proteins our analyses were more in-depth than previous studies. A subset of these studies revealed mechanistic insights which served as seeds for ongoing efforts to derive novel therapeutic avenues (see below).

Abeta-mediated tau-dependent signaling in Alzheimer’s disease

Our Alzheimer disease research program focuses on the earliest steps in the disease.

The prevalent thinking is that Abeta-mediated tau-dependent signaling is initiated when the amyloid beta peptide (Aβ) is endoproteolytically cleaved from the amyloid precursor protein (APP) by an enzymatic complex, known as γ-secretase, comprising either presenilin-1 or presenilin-2 intramembrane proteases.

Once generated, Aβ can assemble into small oligomers that can interact with cells, for example, by binding to the prion protein (PrP). Downstream toxicity then depends on the presence of the tau protein, albeit in poorly understood ways. Discovery work of this nature can reveal unexpected connections between proteins.

Only through extensive validation work is meaning given to these discoveries. The following discoveries from this group have impacted the field’s understanding of the canonical AD pathway:

• Lingo-1 binds to the amyloid precursor proteins (APP), thereby modulating the endoproteolytic production of Aβ from its APP precursor. This was the first study to implicate Lingo-1 in APP biology. A systematic follow-up study corroborated that the Lingo-1-APP interaction stands out (relative to other APP binding candidates) by its robust effect on APP ectodomain shedding.
• Mature gamma secretase complexes comprising presenilin-1 or -2 are embedded in distinct molecular environments. We showed that only presenilin-2 complexes interact with another intramembrane protease, known as signal peptide peptidase (SPP). This work provided strong experimental evidence for a previously proposed concept of the ‘proteasome of the membrane’, according to which intramembrane proteases operate in concert to patrol cellular membranes to rid them of stubs left behind after the endoproteolytic cleavage of transmembrane proteins.
• Identification of the smallest protein known to interact with Aβ. This work established that somatostatin (SST), a 14-amino-acid bioactive cyclic brain peptide, interacts selectively with oligomeric but not monomeric Aβ. Moreover, it showed that Aβ amyloid aggregation can be redirected to the formation of smaller (oligomeric) assemblies in the presence of SST. Because SST is naturally stored as a dense amyloid and its synaptic SST release sites overlap with sites of Aβ generation, these findings may signify a modulating influence of SST on the etiology of AD.
• The first study to document an interaction between PrP and APP. This interaction has since been shown to modulate APP endoproteolysis. More remarkably, PrP has even been proposed to serve as the most critical cell surface receptor for oligomeric Aβ.
• Discovery of profound differences in the interaction of wild-type versus mutant tau—carrying a P301L frontotemporal dementia (FTD) mutation—with non-muscle myosins (NMMs). The study established that binding of tau to NMMs critically depends on the ATPase activity of NMMs not being inhibited. It also showed that the interaction is perturbed in FTD mouse models. It thereby corroborated proposed roles of tau in maintaining dendritic spines and mitochondrial fission biology, two subcellular niches affected early in AD and other tauopathies.

Prion diseases: from evolution through function to disease intervention

The prion protein causes invariably fatal diseases in humans and livestock, including Creutzfeldt-Jacob disease (CJD), Bovine Spongiform Encephalopathy (BSE) and Chronic Wasting Disease (CWD).

In 2009, we discovered the evolutionary origins of the prion founder gene from a family of ZIP metal ion transporters. Subsequently, we established that the emergence of the prion founder gene was an accident of nature, caused by a genomic insertion of a spliced and C-terminally truncated transcript of an ancestral ZIP metal ion transporter.

These discoveries explained characteristics of the prion protein (PrP) as remnants of an ancient function in the sensing and transport of metal ions and provided a compelling explanation for why the protein is embedded in the membrane with a glycosylphosphatidylinositol anchor.

Recognizing that ZIP transporters play a critical role in a cellular morphogenetic program known as epithelial-to-mesenchymal transition (EMT) led us to investigate if PrP inherited an involvement in EMT. Indeed, in 2015, we reported that PrP levels are tenfold upregulated during EMT and its presence is essential for the execution of a signaling loop that controls the polysialylation of the neural cell adhesion molecule 1 (NCAM1), one of the most studied posttranslational modification of any brain protein. This body of work provided critical insights into the physiological function of PrP.

In recent years, we and others have been exploring avenues for reducing levels of the cellular prion protein (PrPC), widely understood to be an effective strategy for delaying prion disease.

These efforts culminated recently in a rational small molecule-based strategy that accomplishes a profound (>50%) reduction of PrPC levels. The goal is to fully develop this therapeutic angle.

Selected Publications

Gerold Schmitt-Ulms, Declan Williams, Mohadeseh Mehrabain, Sepehr Ehsani. The IDIP framework for assessing protein function and its application to the prion protein. Biol Rev. 2021/05/06; Available from: https://doi.org/10.1111/brv.12731.

Alejandro Ruiz-Riquelme, Alison Mao, Marim M Barghash, Heather H C Lau, Erica Start, Gabor G Kovacs, K Peter R Nilsson, Paul E Fraser, Gerold Schmitt-Ulms, Joel Watts. Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice. Acta Neuropath Commun. 2021/05/10; 9(1):83. Available from: https://doi.org/10.1186/s40478-021-01187-6.

Min Wu, Lyudmyla Dorosh, Gerold Schmitt-Ulms, Holger Wille, Maria Stepanova. Aggregation of Aβ40/42 chains in the presence of cyclic neuropeptides investigated by molecular dynamics simulations. PLoS Comp Biol. 2021/03/12; 17(3): e1008771. Available from: https://doi.org/10.1074/jbc.RA120.015389.

Samih Alqawlaq, Izhar Livne-Bar, Declan Williams, Joseph D'Ercole, Sara Leung, Darren Chan, Alessandra Tuccitto, Alessandro Datti, Jeffrey Wrana, Anita Corbett, Gerold Schmitt-Ulms, Jeremy Sivak. An endogenous PI3K interactome promoting astrocyte mediated neuroprotection identifies a novel association with RNA binding protein ZC3H14. J Biol Chem. 2020/11/26; 296(3):100118. Available from: https://doi.org/10.1074/jbc.RA120.015389.

Xinzhu Wang, Erik Friesen, Iris Müller, Mackenzie Lemieux, Ramona Dukart, Isabella B L Maia, Suneil Kalia, Gerold Schmitt-Ulms. Rapid Generation of Human Neuronal Cell Models Enabling Inducible Expression of Proteins-of-interest for Functional Studies. Bio-protocol. 2020/05/05; 10(9):e3615. Available from: https://doi.org/10.21769/BioProtoc.3615.

Mitchell L De Snoo, Erik L Friesen, Yu Tong Zhang, Rebecca Earnshaw , Genevieve Dorval, Minesh Kapadia, Darren M ‘Hara, Victoria Agapova, Hien Chau, Ornella Pellerito, Matthew Y Tang, Xinzhu Wang, Gerold Schmitt-Ulms, Thomas M Durcan, Edward A Fon, Lorraine V Kalia, Suneil K Kalia. Bcl-2 associated athanogene 5 (BAG5) regulates Parkin-dependent mitophagy and cell death. Cell Death Dis. 2019/12/02; 10(12): Available from: https://doi.org/10.1038/s41419-019-2132-x.

Raphaella W L So, Sai Wai Chung, Heather H C Lau, Jeremy J Watts, Erin Gaudette, Zaid A M Al-Azzawi, Jossana Bishay, Lilian Tsai-Wei Lin, Julia Joung, Xinzhu Wang, Gerold Schmitt-Ulms. Application of CRISPR genetic screens to investigate neurodegenerative diseases. Mol Neurodegener. 2019/11/14; 14(1):41. Available from: https://doi.org/10.1186/s13024-019-0343-3.

Xinzhu Wang, Declan Williams, Iris Müller, Mackenzie Lemieux, Ramona Dukart, Isabella B L Maia, Hansen Wang, Amanda L Woerman, Gerold Schmitt-Ulms. Tau interactome analyses in CRISPR-Cas9 engineered neuronal cells reveal ATPase-dependent binding of wild-type but not P301L tau to non-muscle myosins. Sci Rep. 2019/11/07; 9(1):16238. Available from: https://doi.org/10.1038/s41598-019-52543-5.

Michael Solarski, Declan Williams, Mohadeseh Mehrabian, Hansen Wang, Holger Wille, Gerold Schmitt-Ulms. The human brain somatostatin interactome: SST binds selectively to P-type family ATPases. PLoS One. 2019/05/28; 14(5):e0217392. Available from: https://doi.org/10.1371/journal.pone.0217392.

Matthew E C Bourkas, Hamza Arshad, Zaid A M Al-Azzawi, Ondrej Halgas, Ronald A Shikiya, Mohadeseh Mehrabian, Gerold Schmitt-Ulms, Jason C Bartz, and Joel C Watts. Propagation of hamster prions in cultured cells requires cell type-specific factors and is inhibited by mouse prion protein. J Biol Chem. 2019/01/31; 294(13):4911-4923. Available from: https://doi.org/10.1074/jbc.RA118.007135.

Farinaz Ghodrati, Mohadeseh Mehrabian, Declan Williams, Ondrej Halgas, Matthew E C Bourkas, Joel C Watts, Emil F Pai, Gerold Schmitt-Ulms. The prion protein is embedded in a molecular environment that modulates transforming growth factor β and integrin signaling. Sci Rep. 2018/06/05; 8(1):8654. Available from: https://doi.org/10.1038/s41598-018-26685-x.

Seema Qamar, GuoZhen Wang, Suzanne J Randle, Francesco Simone Ruggeri, Juan A Varela, Julie Qiaojin Lin, Emma C Phillips, Akinori Miyashita, Declan Williams, Florian Strohl, William Meadows, Rodylyn Ferry, Victoria J Dardov, Gian G Tartaglia, Lindsay A Farrer, Gabi S Kaminski, Clemens F Kaminsky, Christine E Holt, Paul E Fraser, Gerold Schmitt-Ulms, David Klenerman, Tuomas Knowles, Michelle Vendruscolo, Peter St George-Hyslop. FUS phase is modulated by a molecular chaperone and methylation of arginine cation-π interactions. Cell. 2018/04/19; 173(19): 720-734.e15. Available from: https://doi.org/10.1016/j.cell.2018.03.056.

Michael Solarski, Hansen Wang, Holger Wille, Gerold Schmitt-Ulms. Somatostatin, a new role for an old player in Alzheimer’s disease. Prion. 2018/01/31; 12:1-8. Available from: https://doi.org/10.1080/19336896.2017.1405207.

Jian Hu, Holger Wille, Gerold Schmitt-Ulms. The evolutionary unZIPping of a dimerization motif—a comparison of ZIP and PrP architectures. Pathogens. 2017/12/29; 7(1): 4. Available from: https://doi.org/10.3390/pathogens7010004.

Alexandro Ruiz-Riquelme, Heather Lau, Erika Stuart, Adrienn N Goczi, Zhilan Wang, Gerold Schmitt-Ulms, Joel Watts. Prion-like propagation of β-amyloid aggregates in the absence of APP overexpression. Acta Neuropathol Commun. 2018/04/03; 6(1):26. Available from: https://doi.org/10.1186/s40478-018-0529-x.