12 Apr 2024

Scientists are expanding strategies for targeting misfolded tau. At this year’s AD/PD conference, held March 5 to 9 in Lisbon, Portugal, speakers highlighted a protein modification approach—sumoylation. This post-translational modification adds a small ubiquitin-like modifier (SUMO) to lysine residues. This modifier comes in two main flavors, SUMO1 or SUMO2, which have different effects. Sumoylation has been studied in Huntington’s and Parkinson’s diseases, but so far has received scant attention in Alzheimer’s and other tauopathies.

According to talks in Lisbon, that may be about to change. Ottavio Arancio of Columbia University Medical Center, New York, linked sumoylation to tau pathology, with SUMO1 worsening it, and SUMO2 protecting against it. He noted that tauopathy mice have an abundance of SUMO1-conjugated tau, but a dearth of SUMO2-tau. Luana Fioriti of the Mario Negri Institute of Pharmacological Research in Milan reported that adding SUMO2 to tau prevented its aggregation. This rescued synaptic function and memory in a tauopathy mouse model. Meanwhile, Paul Fraser of the University of Toronto extended the findings to Alzheimer’s, a secondary tauopathy. In a mouse model of amyloidosis, boosting SUMO2 protected synapses. Fioriti’s lab has developed a biologic analog, SBT02, that Fraser said restored synaptic health and memory in mice. The three labs collaborated on these studies.

“SUMO1 and SUMO2 impact tauopathies and amyloid pathology in quite different fashions,” Fraser told Alzforum. “SUMO2 maintains tau in a more soluble state and mitigates the synaptic damage associated with AD.”

Amy Pooler of Sangamo Therapeutics, San Francisco, noted that earlier reports of SUMO1 sumoylation excited the field. “Perhaps surprisingly, these data suggest that SUMO2 appears to have an opposing effect … However, more work will need to be done to understand the underlying mechanism and whether SUMO2 represents an important novel target for treating tauopathies,” she wrote to Alzforum (comment below).

Two Types of SUMO. SUMO1 (left) is shaped differently from SUMO2 (right), with distinct electrostatic potential and hydrophobicity. [Courtesy of Luana Fioriti.]

Sumoylation can change a protein’s shape and stability, as well as influence its interactions with other proteins. It was first implicated in AD about two decades ago, but it was unclear what substrates were altered (Jan 2003 news). Fraser later showed that tau was one, becoming sumoylated at lysine 340, but not other lysines (Dorval and Fraser, 2006). Another group reported that SUMO1 promoted tau phosphorylation and lowered its solubility, causing tau to aggregate (Luo et al., 2014). Fraser generated transgenic mice that overexpress SUMO1, and found they lost synapses and developed memory problems with age (image below; Matsuzaki et al., 2015). 

Even less is known about SUMO2 and tau. Unlike SUMO1 sumoylation, which occurs constitutively, SUMO2 conjugation needs a trigger, such as cellular stress. Arancio noted that 8-month-old PS19 mice, which express mutant P301S tau, have less SUMO2-conjugated tau, and more SUMO1-conjugated tau, than do wild-types. The same held true in neurons generated from a patient with a R406W tauopathy; the cell work was done in the lab of Kenneth Kosik at the University of California, Santa Barbara.

Could increasing SUMO2 conjugation ameliorate tauopathy? Yes, according to Fioriti. When Franca Orsini in her lab expressed SUMO2 in neurons that carried mutant tau, phosphorylated tau and aggregated tau were cut in half. Mutating lysine 340 of tau abolished this protection, demonstrating that tau sumoylation was the key factor. The strategy worked in vivo, too. When Orsini crossed PS19 mice with transgenic mice generated by Fraser that overexpress SUMO2, the offspring had half as much p-tau and insoluble tau as did typical PS19 mice (image below).

Preventing Tau Pathology. P-tau (brown) accumulates in the hippocampi of PS19 tauopathy mice (left), but when SUMO2 is overexpressed (right), less forms. [Courtesy of Rosaria Pascente and Luana Fioriti.]

How does SUMO2 protect against tauopathy? In part, by keeping tau in the right place, Fioriti claimed. In tauopathies such as Alzheimer’s, tau strays into synapses, leading to loss of dendritic spines (Sep 2010 news; Jan 2011 news). In the PS19-SUMO2 crosses, however, tau stayed put on microtubules and the mice maintained as sharp a memory as wild-types, Fioriti said (image below). Many of these findings are summarized in a preprint on bioRxiv (Orsini et al., 2022). 

SUMO2 also rescues flagging mitochondrial metabolism due to tau toxicity, according to Fioriti. Previous studies reported that wild-type tau cozies up to proteins in these cellular powerhouses. Mutant tau does not, leading to sluggish energy production (Dec 2017 conference news; Jan 2022 news; Apr 2023 conference news). Collaborating with Catarina Quinzii at Columbia, Fioriti found that SUMO2 overexpression restored mitochondrial energy production to normal levels in the brains of PS19 mice.

Scientists in Lisbon wondered if the primary effect of SUMO2 is to stop phosphorylation of tau, preventing its misfolding and negative downstream effects. Fioriti said she believes this is the case, but still needs to demonstrate it experimentally.

“It would be interesting to know whether the protective role of SUMO2 is only due to tau sumoylation, or if sumoylation of other proteins contributes to the effects observed,” Tara Tracy at the Buck Institute for Research on Aging, Novato, California, told Alzforum. In Lisbon, Fioriti noted that there are other candidates, such as synaptic proteins, that might play a role as well.

PS19 mice model primary tauopathies such as frontotemporal dementia. Would the same principles hold in models of Alzheimer’s disease, where aggregated Aβ abounds? Fraser addressed this, crossing his SUMO2 mice with APP mice. As in primary tauopathy models, SUMO2 rescued synaptic plasticity and memory. Notably, it had no effect on amyloid. APP-SUMO2 mice had as many plaques as APP controls. “SUMO2 makes synapses resistant to amyloid toxicity,” Fraser concluded.

Fioriti has developed a synthetic protein analog of SUMO2, SBT02, that becomes conjugated to tau in vitro. It readily enters the brain in animal models. When the researchers injected APP mice with 20 mg/kg SBT02 under the skin three times per week from the age of 3 to 6 months, it prevented synaptic damage and memory problems. Could it do as well in mice that had already lost synapses? Fioriti and colleagues injected the drug starting at 6 months, when the animals had established plaques. Three months later, synaptic plasticity, as measured by long-term potentiation in brain slices, was restored to wild-type levels, and memory nearly to that level. “Treatment can rescue damaged and dysfunctional synapses,” Fraser said in Lisbon.

Fraser told Alzforum that the researchers have finished preclinical testing and initial toxicology studies on SBT02, and are preparing to do comprehensive toxicology testing. If all goes well, they plan to advance the biologic to clinical trials.—Madolyn Bowman Rogers

Comments

1. • Amy Pooler
     Sangamo Therapeutics
   • Posted: 12 Apr 2024

   It’s been almost a decade since the exciting initial discovery of tau SUMOylation by SUMO1, which inhibits degradation of tau and promotes its accumulation. However, it is unknown whether other SUMO isoforms have a similar role. Perhaps surprisingly, these data suggest that SUMO2 appears to have an opposing effect, leading to reduced tau aggregation. Interestingly, mutant tau itself may lower SUMO2 expression due to cell stress, which then could further exacerbate tau toxicity. However, more work will need to be done to understand the underlying mechanism and whether SUMO2 represents an important novel target for treating tauopathies.

   View all comments by Amy Pooler
2. • Markus Zweckstetter
     Max Planck Institute for Biophysical Chemistry
   • Posted: 15 Apr 2024

   This highly interesting study supports an important role of sumoylation as a post-translational modification that solubilizes aggregation prone proteins. The study focuses on SUMO2, and it will be interesting to see how modification by SUMO2 compares to modification by SUMO1 with respect to tau pathology in vivo.

   From a therapeutic point of view, it is important to understand the specificity of the chaperoning effect of sumoylation and how this would compare to other approaches that use general cell regulation mechanisms for regulating protein solubility in neurodegenerative diseases.

   View all comments by Markus Zweckstetter

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References

News Citations

1. SUMO-Wrestling with APP? 15 Jan 2003
2. The Plot Thickens: The Complicated Relationship of Tau and Aβ 12 Sep 2010
3. Tau’s Synaptic Hats: Regulating Activity, Disrupting Communication 18 Jan 2011
4. Is There No End to Tau’s Toxic Tricks? 28 Dec 2017
5. Survey of Tau Partners Highlights Synaptic, Mitochondrial Roles 27 Jan 2022
6. By Unleashing Microglial cGAS, Tau STINGs Neurons 26 Apr 2023

Research Models Citations

1. Tau P301S (Line PS19)
2. TgCRND8

Paper Citations

1. Dorval V, Fraser PE. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J Biol Chem. 2006 Apr 14;281(15):9919-24. PubMed.
2. Luo HB, Xia YY, Shu XJ, Liu ZC, Feng Y, Liu XH, Yu G, Yin G, Xiong YS, Zeng K, Jiang J, Ye K, Wang XC, Wang JZ. SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16586-91. Epub 2014 Nov 5 PubMed.
3. Matsuzaki S, Lee L, Knock E, Srikumar T, Sakurai M, Hazrati LN, Katayama T, Staniszewski A, Raught B, Arancio O, Fraser PE. SUMO1 Affects Synaptic Function, Spine Density and Memory. Sci Rep. 2015 May 29;5:10730. PubMed.
4. Orsini F, Argyrousi EK, Restelli E, Ford LK, Takamura H, Matsuzaki S, Zentilin L, Pascente R, Kanaan NM, Soni R, Katayama T, Chiesa R, Forloni G, Kosik KS, Kandel ER, Fraser PE, Arancio O, Fioriti L. SUMO2 Protects Against Tau-induced Synaptic and Cognitive Dysfunction. 2022 Nov 13 10.1101/2022.11.11.516192 (version 1) bioRxiv.

Further Reading

News

1. SUMO versus Ubiquitin: A Fight for Huntington’s Disease? 2 Apr 2004
2. Fighting the SUMO Pathway—Implications for Huntington Disease 22 Nov 2004
3. A Toxic Combo: Huntingtin Specificity Tied to Striatal G Protein 6 Jun 2009
4. New Parkinson’s Gene: DJ Mutations Make Neurons Change Their Tune 22 Nov 2002
5. DJ-1 Dances with Daxx to Keep Neurons Spry 5 Jul 2005
6. Taos: Not the Usual Suspects: PARIS et al. Mark Progress in PD 28 Apr 2011
7. Activity-Dependent Control of Synapses—MEFs Muffle, Integrins Integrate 21 Feb 2006
8. New Pathways With Promise in AD—An Inflammatory Statement? 26 Sep 2009