From Cells to Siamese: Advancing Our Understanding of Cognitive Dysfunction

siamese-cat

Guest post by Ingrid R. Niesman, MS PhD

Anyone who has lost a beloved relative or cherished pet to dementia knows the tremendous personal cost. My phone and computer screens still display 19 year-old Mr. Spock, although he left us in October of 2013. His last years were marked with curious Parkinson’s disease-like symptoms, most notably tremors, loss of appetite and a pronounced head tilt. However, he maintained his dignity and profound loving nature to the end. It was the beginning of my personal journey to understand feline cognitive dysfunction syndrome (CDS), although I had no concept that such a clinical condition even existed.

siamese-cat

Mr. Spock

When does curiosity spur action?

It takes a big leap of faith and significant creativity to start working on a novel scientific idea from scratch. I began by designing experiments to understand why my Siamese cat seemed predisposed to neurodegeneration. I have no background in feline health or medicine. I do, however, have a lengthy career as a cell biologist and neuroscientist. I observed a phenomenon and did my homework. In previous posts, I have described how a single mutated gene, tyrosinase, confers (or as I like to tell students – confurs) the beautiful coats of purebred Siamese cats. Fur and brains seem disconnected. Yet, embryonically, the cells that generate skin pigments and certain brains cells share identical lineage. If tyrosinase doesn’t work in warm areas of Siamese skin, then the protein will also not function in brain cells. Similar mutations in human tyrosinase are known to disturb normal cell physiology but this mechanism has not been studied for the Siamese mutation. YET!

team-siamese

Putting my skill set to work

What my team and I have done is to use a combination of molecular biology and light microscopy to figure out if Siamese tyrosinase is potentially harmful when expressed in cells that normally wouldn’t produce this protein. We have spent the past 18 months preparing to test our cloned DNA in the infamous human cell line, HeLa. We had the normal and Siamese version of tyrosinase synthesized and then designed circular DNA snippets that add a green tag (GFP) to either the beginning of tyrosinase protein or the end of the protein. Using these pieces of DNA as templates, HeLa cells make feline protein that we can see microscopically or biochemically. These are early days, but our cell-based system is working as we expect. We have achieved robust and reproducible protein expression. More importantly, we have also found evidence that Siamese tyrosinase is degraded at a faster rate than normal feline tyrosinase. When we treat tyrosinase-expressing cells with chemicals that block this degradation, we find large clumps of protein in our Siamese tyrosinase expressing cells. Aggregated proteins clog normal cell functions and can lead to cell death if the biochemical equivalents of waste disposal are overwhelmed. Much confirmatory work is required before we can publish these findings but they support our original suggestion that Siamese tyrosinase is toxic.

siamese-cell-biology

From cells to cats to people

Developing disease therapies is a laborious and expensive undertaking. Finding the precise compound to alter disease progression or improve symptoms starts by creating models of the disease in cells. Currently, my team and I are developing cells that mimic what happens to Siamese neurons if their mutant protein is expressed and causes damage. Logically, our next steps would be to look for drugs that could ease or stop the damage from occurring. All this work is before we even think about a whole animal. Although it seems like a shot in the dark, we have already mapped out several cellular networks we believe will make good therapeutic targets. The quest for the elusive perfect animal model of neurodegeneration is heating up, as the rise of cognitive dementia in humans and cats is exploding. This is where we are in our journey of discovery towards this goal.

Ingrid R. Niesman MS PhD is the Director of the SDSU Electron Microscope Imaging Facility at San Diego State University.

4 Comments on From Cells to Siamese: Advancing Our Understanding of Cognitive Dysfunction

  1. Ingrid Niesman
    October 30, 2019 at 11:46 am (2 months ago)

    Dear Marge
    Thank you for your reply. Yes, CDS is prevalent among all cats. My interest is Siamese, specifically because I believe we have a mechanism through the mutated tyrosinase that starts their decline and pathology. As scientists, we like to find a “root” cause that may be modified by therapies . Our finding can then be extended to all.

    Reply
    • Marge
      October 30, 2019 at 12:00 pm (2 months ago)

      Although it won’t help our situations now, if some treatment can be found and “extended to all”, cats, dogs, people, that would be great! There is such a tsunami of people developing various dementias, some who are not even retirement age yet! While I would prefer neither my kitty nor my mother (or anyone else!) had this, at least they got good long years in beforehand! Per one web site, Miss Katie is now actually older than my mother. She is still a handful though – had to trim her nails and did she put up a fight, even with a grooming bag and blanket over her!

      I do wish you great strides in your endeavor to find a cause and maybe a cure.

      Reply
  2. Connie Fischer
    October 30, 2019 at 9:55 am (2 months ago)

    This is just fabulous research! We want to find cures for humans and our precious fur babies as well. Thank you so much for your hard work and determination. God bless you!

    Reply
  3. Marge
    October 30, 2019 at 9:37 am (2 months ago)

    Currently my 20+ yo has what I believe is feline cognitive disfunction, aka dementia. She will stare at the wall, doors, litter box or just space in general, sometimes accompanied by yowling and sometimes gets rather agitated (equivalent to what they call sun-downing in people with dementia.) My 96 yo mother also has this lovely condition. I am surprised my 20+ yo is still ticking along – identified early CKD in July 2015, hyperthyroid March 2016, radioIodine treated Feb 2017, lung spots found April 2018 and she developed this dementia-like condition this year. Still eating well, using litter, getting around (stumbles a bit, but she has lost some muscle mass due to age), so whatever she wants, she gets! If she makes it until late winter/early spring, she will be 21. She isn’t Siamese BTW. Dementia knows no age or ancestry, although often medical conditions can show some predisposition in certain “breeds.” In Katie’s case, it could be age related, it could be the growths in her lungs have spread to her brain. Who knows? For the most part, we are done with vet intervention on her. She always takes the ride hard (pukes every time) and there really isn’t anything they can do.

    On the flip side, we suddenly lost a 15 yo last year (possible kidney tumor, big kidney/little kidney syndrome) and we’re about to lose another. We don’t have the fluid results yet, probably will get that later today, but she was not eating well, rather lethargic and part of initial exam revealed Ascites, fluid build up in the abdomen. Several conditions have been ruled out, so potentially she could have FIP or Carcinomatosis (possibly lymphoma.) She is only 13.

    Mr. Spock was a handsome guy! Also, making it to 19 is quite an achievement. Prior to my Katie, the oldest was 16. Some were lost to other conditions at 10, one even at about 6-7, due to dental anesthesia. 🙁 So many diseases and hazards – personally I would rather read/learn about them than learn the way I am learning. Every one lost was due to something different.

    Reply

Leave a comment

First time visitors: please read our Comment Guidelines.