Tag Archives: mitochondria

An ALS/PSP alliance?

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A development in amyotrophic lateral sclerosis (ALS; Lou Gehrig disease) may have welcome implications for PSP.

A tiny drug company based in Blue Bell, PA called Mitochon Pharmaceuticals just announced having won a $1 million grant from the ALS Association to mount a Phase II, double-blind trial of their drug in ALS.  The company expects the trial to kick off in early 2027, with a six-month double-blind period.  That means that the result should be available in late 2028 (my own optimistic estimate). 

The drug, known as MP-101 or 2,4-dinitrophenol, is given as an oral capsule and exerts multiple actions in the brain.  Chief among these is to correct leaks in the membrane enclosing the mitochondria, the cells’ power plants where sugar and oxygen come together to produce energy.  PSP has a similar problem with its own mitochondria.  While it’s not as important in PSP as in ALS, it’s possible that neutralizing one important such issue could have a calming effect on the whole self-reinforcing cycle of damage. That’s why Mitochon is interested in testing MP-101 in PSP as well. But so far, they have been unable to raise financing for a PSP trial and have no other drugs on the market to provide that capital.

What probably swayed the ALS Association in deciding to support the Phase II trial was spinal fluid results from Mitochon’s much smaller (10 patients) and shorter (2 weeks) ALS trial, where MP-101 reduced levels of neurofilament light chain (NfL).  That’s a protein released into the spinal fluid and blood in multiple conditions involving rapid loss of axons connecting brain cells, including those in PSP.  While the NfL level, therefore, is a diagnostic marker and not part of the problem itself, it holds promise as a sensitive way to detect benefit from an experimental drug.  Demonstrating such an effect would require far fewer patients and/or dollars than relying on any imaging procedure or neuro exam result. 

There are other biological similarities between ALS and PSP despite the fact that ALS is mostly a disease of the spinal cord and PSP is mostly a disease of the basal ganglia and brainstem:

  • Aggregates of the protein TDP-43, the equivalent of the tau aggregates of PSP, occur in the spinal cord in nearly half of all people with PSP, often in the same set of cells as in ALS.
  • Both diseases include important defects in the brain cells “garbage disposal” systems.
  • Both have problems coordinating the transport of vesicles around the cell.  Those are tiny bubbles of membrane with chemicals that are made in one part of the cell but needed elsewhere.
  • Inflammation is important in both, and in both ALS and PSP it involves the microglia, which are the “white blood cells” of the brain and spinal cord.
  • The first and most important genetic risk factor in PSP, called the tau H1 haplotype, is also associated with ALS despite the fact that the latter is not a tau-based disorder.  (The same is true for Parkinson’s disease.)
  • Both diseases can involve the frontal cortex, producing “executive dysfunction” as a cognitive symptom.

Here’s what I hope: 

  • I hope that MP-101 will be spectacularly successful in slowing the progression of ALS, which is just as disabling as PSP but starts 20 years younger, on average, and is fatal after an average of only three years.
  • I hope that funders with pockets as deep as those of the ALS Association will take a cue from that fine organization and fund a trial of MP-101 in PSP. 

For the scientists among you, here’s Mitochon’s brief but technical explanation of the mechanism of action of MP-101, lightly edited by me:

MP101 is a mitochondrial uncoupler, 2,4-dinitrophenol (DNP), a weak acid with a dissociable proton. The pharmacology of MP101 is unique in that it involves a transfer of proton (H+) into the pH-basic mitochondrial matrix, a non-genomic event. This event involves: 1) lowering damage by reducing ROS production and calcium overload, while 2) promoting repair with the induction of cAMP production, activation of CREB and production of BDNF.

For a far more detailed review by John Geisler, PhD, co-founder and chief scientific officer of Mitochon, see this link. As you’ll read, Dr. Geisler has more ambitions for the drug than just ALS and PSP.

Disclosure: I have consulted for Mitochon in the past but have never had, and do not have, a financial interest in the success of the company.

Under the hood

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In response to a reader’s request, here’s a brief description of the mechanism of action of Relyvrio, which is a combination of two drugs, sodium phenylbutyrate and taurursodiol.  The text in bold italics below is copied verbatim from the supplementary material attached to the publication reporting the results of the first ALS trial.  The same explanation applies to PSP and other neurodegenerative diseases. You may feel that any treatment that claims to address all of those complex diseases is claiming too much, and you could be right. But stranger things have happened. If you want more scientific detail, see the five references below. Note that Reference 5 discusses release of cytochrome C from mitochondria. That’s a cell signalling compound that causes cells to start up their “suicide machine,” more formally called the apoptotic pathway. Cells undergo apoptosis when they’re not working well or as a normal “pruning” procedure during growth and development. Taurursodiol prevents that from happening as easily.

Endoplasmic reticulum stress or dysfunction associated with protein misfolding and aggregation has been implicated in the pathogenesis of ALS,[1] as has disruption of mitochondrial function and structure.[2] Sodium phenylbutyrate is a histone deacetylase inhibitor that has been shown to upregulate heat shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress.[3,4] Taurursodiol recovers mitochondrial bioenergetic deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the apoptotic threshold of the cell.[5]

1. Jaronen M, Goldsteins G, Koistinaho J. ER stress and unfolded protein response in amyotrophic lateral sclerosis—a controversial role of protein disulphide isomerase. Front Cell Neurosci 2014;8:402.

2. Mehta AR, Walters R, Waldron FM, et al. Targeting mitochondrial dysfunction in amyotrophic lateral sclerosis: A systematic review and meta-analysis. Brain Commun 2019;1:fcz009.

3. Kaur B, Bhat A, Chakraborty R, et al. Proteomic profile of 4-PBA treated human neuronal cells during ER stress. Mol Omics 2018;14:53-63.

4. Suaud L, Miller K, Panichelli AE, Randell RL, Marando CM, Rubenstein RC. 4-Phenylbutyrate stimulates Hsp70 expression through the Elp2 component of elongator and STAT-3 in cystic fibrosis epithelial cells. J Biol Chem 2011;286:45083-92.

5. Rodrigues CM, Solá S, Sharpe JC, Moura JJ, Steer CJ. Tauroursodeoxycholic acid prevents Bax- induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry 2003;42:3070-80.

The mighty-chondria

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When someone with PSP reports a feeling of “weak muscles” to their neurologist, the answer is typically, “yes, you’re weak, but the problem isn’t in your muscles – it’s in the messages to your muscles from your brain.”  But it turns out that in PSP, muscles can be a problem, too, and that opens up some treatment potential.

We’ve known for decades that the mitochondria aren’t working right in PSP and other neurodegenerative diseases.  You’ll recall that those are the tiny factories in almost all our cells devoted to the biochemical process of respiration – that where oxygen and sugar combine to produce energy for the cell’s many functions.  Besides that very important job, mitochondria are also involved in processes such as neural plasticity (the ability of brain cells to react to external influences), calcium regulation, electrical properties of the cell and synaptic transmission.

Here’s a electron microscope photo of a single mitochondrion (from this source).

What brain cells and muscle cells have in common is the need to maintain very different concentrations of potassium between themselves and the surrounding fluid (called a “gradient”), and that takes lots of energy.  So, any defect in mitochondria will tend to hurt brain cells and muscle cells first and worst.  In fact, childhood neurological dysfunction and muscle weakness are the two main features of a whole category of diseases caused by single-gene mutations affecting proteins used only by mitochondria.

In PSP, the mitochondrial problem is more subtle, but we don’t know exactly what it is or what causes it.  Here are some strands of evidence:

  • Brain cells growing in a dish that have had their own mitochondria destroyed and replaced by mitochondria isolated from blood cells of people with PSP don’t recover from various kinds of stress as well the same brain cells with replacement mitochondria from healthy people. 
  • Toxins damaging an important series of chemical reactions in the mitochondria called Complex I can cause a PSP-like condition in lab animals. 
  • Complex I and other components of mitochondria are also damaged by tau molecules with an abnormal number or location of attached phosphate molecules (“phospho-tau”), which we know occur in PSP.  The net effect is excessive levels of “free radicals,” which are toxic by-products of normal respiration.
  • While the most important gene mutation contributing to PSP risk is in MAPT, which encodes tau, the next-most important is PERK (protein kinase RNA-like endoplasmic reticulum kinase), which regulates the responses to stress in mitochondria.
  • Coenzyme Q-10, a nutritional supplement that assists Complex I, may help some of the immediate symptoms of PSP, as shown by at least one double-blind trial.

All the above is simply background justification to suspect that muscles and not just brain should be involved in PSP.  But there’s more direct evidence, too:

  • Muscle weakness and fatigue are more common in PSP than in others of the same age.
  • Weight loss is common in PSP and occurs early in the disease course.  The same is true for both in Parkinson’s, but not as markedly.
  • Grip strength is impaired in PSP.  That could be a result of changes in the brain, but the duration of the muscle fiber contractions is prolonged in PSP, a sign of muscle dysfunction.
  • Men (but, oddly, not women) with PSP have a reduced overall muscle mass relative to others of the same age. 
  • Muscle biopsy in people with PSP shows modest evidence of the same severe change in mitochondria (called “ragged red fibers”) that occur in the genetic mitochondrial diseases of childhood.

So, what’s the take-home for people with PSP? 

  • First, EXERCISE – including low-intensity muscle-building exercises.  Discuss the details first with your neurologist or physical therapist, and probably also with your primary care physician to make sure your heart and lungs are up to the task. 
  • Second, HAVE HOPE that insights into the mitochondrial role in PSP will bring new treatment or neuroprotection targeted at those cellular processes in the brain.  In fact, one such medication, called AMX-0035 (a combination of taurursodiol and sodium phenylbutyrate) will be entering a Phase 3 trial for PSP in the next few months.  The combination under the brand name “Relyvrio” was approved last year by the FDA for Lou Gehrig disease, where there’s a similar mitochondrial problem, so I have very high hopes that the same will happen for PSP.

Six horsemen of the Apocalypse

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I watched a scientific presentation today in which the speaker started off by summarizing the leading theories of PSP’s pathogenesis.  That means not the external influences such as the genes received from one’s parents or whatever toxins or other stresses might help cause PSP in susceptible people.  Rather, it means the abnormal processes set in motion and operating inside in the brain cells leading to their dysfunction and eventually, their death. 

Here’s a quick rundown for you:

  • Tau splicing.  The tau protein is encoded by the MAPT gene, which has 14 sections called exons encoding separate fragments of the final protein.  These protein fragments are then stitched together, but sometimes one or more of them is omitted by design.  In healthy people, the product of exon 10 is included in about half of the final tau molecules, but in the tau tangles of PSP, that fragment is nearly always included.  This makes the tau more likely to aggregate.
  • Tau post-translational modifications. Many or most proteins have very small molecules attached to them at specific points to regulate their function and direct their folding pattern.  The abnormal tau of PSP has phosphate and other molecules in inappropriate places.  This could help explain the abnormal folding, which in turn produces toxic aggregates.
  • Tau degradation. The normal “garbage disposal” systems of brain cells gets rid of proteins or organelles (the tiny structures in cells that perform specific functions) that are either overproduced, defective or just worn out.  There are two basic kinds of such systems, the ubiquitin-proteasome system and the autophagy-lysosomal system.  Neither works as well as it should in PSP.  This allows abnormal tau and other toxic molecules to accumulate.
  • Intracellular tau spread. In many neurodegenerative diseases, the abnormally folded tau can travel from one brain cell to another, causing normal copies of those molecules to misfold in a similar fashion.  This creates a kind of chain reaction spreading the damage widely. The misfolding pattern of the tau is specific to each of the tauopathies.
  • Mitochondrial dysfunction. The mitochondria are the organelles in the cells that harvest energy from sugars with the help of oxygen.  In PSP, they function abnormally, possibly because of their own genetic mutations, possibly because their biochemistry is particularly sensitive to certain toxins in our environment.  Mitochondrial dysfunction doesn’t just deprive the cell of energy – it also produces toxic compounds such as free radicals that damage other cell components.
  • Gene expression errors. The most recently discovered pathomechanism has to do with abnormal regulation of access of the cell’s protein-making machinery to the DNA “blueprint.” That process is normally regulated by proteins collectively called “chromatin,” which coat and intertwine with the DNA in the nucleus.   One way the abnormality might work is that abnormal chromatin permits inappropriate access to certain genes that stimulate the immune system, producing a harmful inflammatory reaction in the brain.

All of these pathogenetic mechanisms except the first are currently being addressed by drugs in advanced stages of the development pipeline.  I really don’t know which horse to put my money on.