Study demonstrates role of gut bacteria in neurodegenerative diseases

Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are all characterized by clumped, misfolded proteins and inflammation in the brain. In more than 90 percent of cases, physicians and scientists do not know what causes these processes to occur.

Robert P. Friedland, M.D., the Mason C. and Mary D. Rudd Endowed Chair and Professor of Neurology at the University of Louisville School of Medicine, and a team of researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid that have structural similarity to brain proteins leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS.

Alpha-synuclein (AS) is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Friedland has hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. He also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain.

The research, which was supported by The Michael J. Fox Foundation, involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of AS in the intestines and the brain and increased cerebral AS aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of AS aggregates, compared with nematodes not exposed to the bacterial amyloid. A research group led by neuroscientist Shu G. Chen, Ph.D., of Case Western Reserve University, performed this collaborative study.

This new understanding of the potential role of gut bacteria in neurodegeneration could bring researchers closer to uncovering the factors responsible for initiating these diseases and ultimately developing preventive and therapeutic measures.

“These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer’s disease, Parkinson’s disease and ALS,” Friedland said. “This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut.”

Friedland is the corresponding author of the article, Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans, published online Oct. 6 in Scientific Reports, a journal of the Nature Publishing Group. UofL researchers involved in the publication in addition to Friedland include Vilius Stribinskis, Ph.D., Madhavi J. Rane, Ph.D., Donald Demuth, Ph.D., Evelyne Gozal, Ph.D., Andrew M. Roberts, Ph.D., Rekha Jagadapillai, Ruolan Liu, M.D., Ph.D., and Richard Kerber, Ph.D. Additional contributors on the publication include Eliezer Masliah, M.D., Ph.D. of the University of California San Diego.

This work supports recent studies indicating that the microbiota may have a role in disease processes in age-related brain degenerations. It is part of Friedland’s ongoing research on the relationship between the microbiota and age-related brain disorders, which involves collaborations with researchers in Ireland and Japan.

“We are pursuing studies in humans and animals to further evaluate the mechanisms of the effects we have observed and are exploring the potential for the development of preventive and therapeutic strategies,” Friedland said.

C. instagram by Meredith Wright

The hilariously named C. instagram shows C. elegans worms eating E. coli, which they gorge on before clumping together in these patterns. Meredith Wright caught the phenomenon using her smartphone—hence the name of the photo. “I’ve since shared the photo on social networking sites and have had friends who’ve never been interested in biology ask me more about my work because of this photo,” she explains. “To me, this image represents the simple pleasure of finding something beautiful when you don’t expect to, and it shows how easy it is to connect science with new audiences by simply clicking ‘share.’”

So you want to die. So you’ve been eyeing the Drano under the sink. So you’ve been looking at your arteries like highways you could cleave with airplane-wing
steak knives.
So you’ve written about six different suicide notes and none of them says goodbye without actually saying goodbye in the perfect way.
So you’ve been Googling bridges.

I’m nodding. You’re clenching your fists. I know with the pain
even the bacteria in your intestines are tornadoed asunder.
But let’s stop comparing ourselves to natural disasters when we both know
you’re nothing like one. I promise not a mention of stars or ribcages. Drop the poetic
and let’s look each other in the eyes.

Wanna hear a name you should never give a child? Caenorhabditis elegans. It’s the roundworm.
They call it C. elegans on the streets. Every single roundworm has exactly 959
cells. Of 959
cells, 131 cells self-destruct. Scientists have mapped
the fate and the lineage of each and every one. This is non-negotiable.
Every roundworm on the face of the planet has exactly 959 cells and of them
131 cells will die. That cellular ceremony is called this.

This is not a biology textbook, but according to Barbara
Conradt and Ding Xue in “Programmed cell death” (wormbook.org), “Programmed cell death is an integral component of C. elegans development. Genetic studies in C. elegans have led to the identification of more
than two dozen genes that are important for the specification of which cells should live or die, the activation of the suicide program, and the dismantling and removal of dying cells.”

I know what’s underneath your tongue, tangoing
between your teeth: “I want to, but I can’t.” “I wish I could fight.”
“I’m so tired.” “My knuckles are broken open, decades fell into them,
my throat hurts, I want to close my eyes, I am numb. I am numb. I am numb.”
I know. I know because they’ve been underneath my tongue and sometimes still are.
I know because I’ve wondered what Drano tastes like.
I know because there’s still numbness between my toes.

And I know there is no combination of words, no right spin
to your master lock, no deadbolt thrown hard enough to keep you from the fogs.
But maybe this pain is a rite. Maybe this confusion, this numbness, this evolution into a streetlamp
is non-negotiable. Maybe this
is an integral component of your development, maybe there is a specification
of which parts of you should live or die, the activation of the suicide program,
the dismantling and removal of cells that chant dumb ways to die in your ear.
Maybe this is something to toughen your molars
and sharpen your jawline.

I know that it’s piercing the flesh around your spine, dipping into the
waters in you, that you’re coming to a standstill. So uncap the Drano. Stand
on that bridge. Pick up the blade. Maybe coming facefirst to this edge will reveal
the vastness of the space behind you. Maybe this
was programmed into you. The question is. Will you stay in this nightmare til it dissolves.
Will you keep clenching your fists. Creep to the edge. Look over it.
I won’t tell you to stay because I know you can’t.
I will tell you to grope desperately in the dark for a hand, and hold it like
an extra joint when you find one, because it will stay when you can’t. And anchor
the both of you down.

This is the apoptosis: you were not programmed to die in total, so
do not pull that trigger.
Not even C. elegans destroys itself completely. There are parts of you that
need to be swallowed whole, but only 131.
959-131 means 828 parts still studding your artery walls.
You may be breaking, but not all of you. When the winds come to sweep you up,
find roots and slip your limbs beneath them. Because I tell you this. Death
wants you completely. But you are not meant to be dissolved in total.
This is not how. This is not. This is not your deathtime.
This is apoptosis, breather. So breathe. Lose air sometimes, but breathe. Breathe.

—  Apoptosis (a proposal to the suicidal) | kira tang
New treatment hope for Amyotrophic Lateral Sclerosis

A previously unknown link between the immune system and the death of motor neurons in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, has been discovered by scientists at the CHUM Research Centre and the University of Montreal. The finding paves the way to a whole new approach for finding a drug that can cure or at least slow the progression of such neurodegenerative diseases as ALS, Alzheimer’s, Parkinson’s and Huntington’s diseases.

The study, published in Nature Communications, shows that the immune system in the animal model C. elegans, a tiny 1 mm-long roundworm, plays a critical role in the development of ALS. “An imbalance of the immune system can contribute to the destruction of motor neurons and trigger the disease,” said Alex Parker, CRCHUM researcher and Associate Professor in the Department of Neuroscience at the University of Montreal.

Amyotrophic lateral sclerosis is a neuromuscular disease that attacks neurons and the spinal cord. Those affected gradually become paralyzed and typically die less than five years after the onset of symptoms. No effective remedy currently exists for this devastating affliction. Riluzole, the only approved medication only extends the patient’s life by a few months.

More than a dozen genes are related to ALS. If a mutation occurs in one of them, the person develops the disease. Scientists introduced a mutated human gene (TDP-43 or FUS) into C. elegans, a nematode worm widely used for genetic experiments. The worms became paralyzed within about 10 days. The challenge was to find a way of saving them from certain death. “We had the idea of modifying another gene—tir-1—known for its role in the immune system,” said Julie Veriepe, lead investigator and doctoral student under the supervision of Alex Parker. Results were remarkable. “Worms with an immune deficit resulting from the tir-1 gene’s mutation were in better health and suffered far less paralysis,” she added.

This study highlights a never previously suspected mechanism: even if the C. elegans worm has a very rudimentary immune system, that system triggers a misguided attack against the worm’s own neurons. “The worm thinks it has a viral or bacterial infection and launches an immune response. But the reaction is toxic and destroys the animal’s motor neurons,” Alex Parker explained.

Is the same scenario at work with people? Most likely. The human equivalent of the tir-1 gene—

SARM1—has proved crucial to the nervous system’s integrity. Researchers think the signalling pathway is identical for all genes associated with ALS. This makes the TIR-1 protein (or SARM1 in humans) an excellent therapeutic target for development of a medication. SARM1 is particularly important because it is part of the well-known kinase activation process, which can be blocked by existing drugs.

Alex Parker’s team is already actively testing drugs that have been previously approved by the US Food and Drug Administration for treatment of such disorders as rheumatoid arthritis, to see if they work with ALS. Obstacles still remain, however, before finding a remedy for curing or slowing the progression of amyotrophic lateral sclerosis. “In our studies with worms, we know the animal is sick because we caused the disease. This allows us to administer treatment very early in the worm’s life. But ALS is a disease of aging, which usually appears in humans around the age of 55. We do not know if a potential medication will prove effective if it is only given after appearance of symptoms. But we have clearly demonstrated that blocking this key protein curbs the disease’s progress in this worm,” Alex Parker concluded.

Ode to a nematode

In the pantheon of animal models upon which basic scientific research relies, no species stands taller (metaphorically speaking) than Caenorhabditis elegans, a tiny worm (just one millimeter in length) that is broadly used to study fundamental molecular, cellular and developmental  processes in animals.

Nobel laureate Sidney Brenner was among the first to promote the nematode’s utility as a model organism in the early 1960s for a variety of reasons: It is simple. Its entire neural system consists of exactly 302 neurons. It’s easy and cheap to grow in large numbers – and you can freeze the worms, and then thaw them out for later use. And it’s transparent, making it all the easier to peer at the worm’s internal workings. 

C. elegans was the first organism to have its genome completely sequenced in 1998. An adult hermaphrodite worm contains 20,470 protein-coding genes, only slightly less than the estimated total for a human being.

In recent years, scientists have begun creating systemic catalogs of how these genes function and interact, not just in C. elegans but in other model organisms as well. Some of this research is being done by researchers Karen Oegema, PhD, a professor of cellular and molecular medicine and head of the Laboratory of Mitotic Mechanisms in the Ludwig Institute for Cancer Research at UC San Diego and her colleague, Rebecca Green, PhD.

Rather than studying individual cells, Oegema, Green and co-workers look at the effect of gene inhibitions in the structure of a complex tissue. Sometimes, it results in an eye-popping picture. The image above reveals the architecture of C. elegans’ reproductive tissue – its gonads. Red fluorescent markers highlight cell boundaries; green markers indicate DNA.


EDIT: Wow tumblr, thanks for eating my whole description.

My C. elegans recently outgrew his little vial, so these are some pictures of me transferring my fat happy baby into a bigger container. c:
He’s actually a lot more docile and confident than I expected, and he was totally cool with being handled. EATS LIKE A MONSTER AND DOESN’T AFRAID OF ANYTHING. So I think after another moult or two I’ll start handling him once a week for a few minutes to get him more accustomed to it, and see how he does. He might make a better “hand” tarantula than I anticipated!
He’s grown so much, too. I seriously can’t get over it. I’ve only had him for less than 5 months, and he was under 0.25" when I got him. I’M SO PROUD.

A comedy act at a C. elegans conference, to which my genetics professor was a witness. (Guys. They have comedy routines at C. elegans conferences) :
  • Researcher 1: You know those Australian sheepskin boots? UGG boots?
  • Researcher 2: Oh yeah! Tryptophan boots!
  • Researcher 1: Well...why don't they make UGA boots?
  • Researcher 2: Why, that would be nonsense!

El Harlem Shake más biológico que he visto hasta ahora

Enviado por Liphistius, buen tumblero y mejor persona


For all those Microbiologists…


So here are a few of the high points of my research for this summer! I’ve been looking at the nematode Caenerhabditis elegans and their excretory cell morphology in exc and similar mutants.

1. The first picture is of our wild type control- BK36- which is just a line of worm that has its excretory cell marked with green fluorescing protein (GFP) and allows for easier imagine (b/c without GFP taking photos of the excretory cell is the more frustrating thing).

2. This here is a BK36 worm with erm-1 knocked down in it. Inerm-1 mutants tubular cells, mainly the intestine and excreotry cell in this case develop abnormally. The canals of the cells here are severely shortened, widened, and definitely cystic so the RNAi trial that we performed to get these mutants worked!

3. Here’s an exc-7 mutant from an exc-7 line crossed with BK36! These mutants have canals about half the length of wild type cells with small cysts running down the canal and usually end in a ball of larger cysts.

4. And here’s what happens when you take and exc-7 worm and knock down erm-1 in them! In the more severe cases, the canal just doesn’t extend when the worm is developing and you get these kinds of excretory cells!

5. This here is an exc-9 that had a phenotype severe enough to image without fluorescence! In these mutants, cysts are very large and occur mostly at the cell body, with a few larger ones occurring farther down the short canal. It looks so cool in the DIC microscope!

6. My pride and joy: an exc-9 x BK36 cross. This was the one cross that I got right on the first try and was needed so now my lab is using this cross! I’m so glad it turned out fine…

7. Here’s another BK36 worm (zoomed out- on a completely different scale than the previous 6) which shows typical body shape. Now compare it to the next picture…

8. Finally, here’s a (zoomed in) picture of worm from the RNAi-sensitive strains eri-1 with the dpy-11 gene knocked out! dpy-11 mutants are usually pretty short and fat, but the RNAi-sensitive strains made these ones particularly so. They’re so cute in the more sensitive strains…

So yeah, these are just some of the highlights of the stuff I did! If you have any questions about anything (like the genes involved of my methods), please contact me and I’ll get back to you! I’m going to be giving a poster of this stuff on Friday so I’m SO PUMPED

ALSO! These photos are mine (i.e. I picked them, put them onto slides, and the sat hunched over them in a dark room and cursed at them until they stopped moving too fast for me to photograph) so I’m not redistributing someone else’s data.