Tag Archives: pedunculopontine nucleus

It’s that pedunculopontine nucleus again. (5CP, part 2)

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My last post described the first two of five new (as of yesterday) publications on PSP to suddenly appear on my routine PubMed search.  The third one is sufficiently interesting and complicated to deserve its own post.

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Falls are perhaps the earliest-appearing and most disabling feature of PSP, but we don’t yet fully understand which of the many brain areas involved in PSP deserves most of the blame.

A PSP-like illness endemic to the islands of Guadeloupe and Martinique is called Guadeloupean tauopathy or Caribbean Parkinsonism (CAP).  It may be the result of consuming two fruits, sweetsop and soursop, which have high levels of a mitochondrial toxin called annonacin.  Injected into rats in a lab, annonacin produces a PSP-like illness complete with abnormal tau accumulation.  However, the human CAP illness includes multiple aggregating proteins in addition to tau.  

The new article from neurologists in Paris and on Guadeloupe and Martinique reports on careful measurements of atrophy of specific brain regions on MRI in 16 patients with CAP, 15 with PSP-Richardson syndrome and 17 healthy, age-matched control participants.  They correlated the results with 11 standard scales assessing gait, general movement and cognitive function and also with electronic measures of gait and eye movement.  The group’s senior leader was Dr. Annie Lannuzel of INSERM, France’s equivalent of the NIH.  She has a long record of research in CAP.  The first author was Dr. Marie-Laure Welter, also of INSERM.

The results were that PSP and CAP differed in their anatomical patterns of brain atrophy.  Although their overall average disease severity was similar, CAP had more cognitive loss with correspondingly more atrophy of cerebral cortex.  On the other hand, the PSP group had more gait instability with correspondingly greater involvement of the midbrain and cerebellum.

The overall statistical comparisons showed that the main source of the gait and balance problem in PSP is damage to the supplementary motor area – pedunculopontine nucleus (SMA-PPN) network.  In CAP the gait/balance problem includes the SMA-PPN but with a major contribution from areas serving general attention and self-awareness.

The SMA is an area of frontal cortex just in front of the primary motor cortex.

The PPN is a complex nucleus at the pons-midbrain junction (PMJ, below):

Here’s why this paper’s results could be important: 

The SMA, as you can see from its superficial location, is an easy target for non-invasive magnetic or electrical trans-cranial stimulation.  TCS is still in its infancy but is starting to show some modest benefits for some movement and cognitive disorders.

The PPN has long been known to be important to the balance issue in PSP and Parkinson’s.  This new research result focuses attention on that nucleus as a potential target for deep-brain stimulation or as a target for surgically implantable stem cells or viral vehicles of genes for depleted enzymes.  Dr. Stuart Clark and colleagues at The State University of New York, Buffalo have already created an experimental model of PSP in rats by altering the function of the PPN.  The results from Welter et al tend to validate the relevance of that model to PSP.  

Rats join the fight

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The best animal model we’ve had for PSP over the last 20 years has been a mouse genetically engineered to carry a mutated human tau gene.  The mutation is typically one of two single-nucleotide substitutions, each found in a form of hereditary frontotemporal dementia.  Such a model has been convenient and productive.  But it would be preferable for a PSP model that a) is in a species with a brain whose circuitry is a bit closer our own, and b) to more closely mimic the pathology of human PSP.  A vivid illustration of the inadequacy of the tau mouse has been the recent failure of two anti-tau antibodies to help human PSP after clear success in slowing progression of pathology in the tau mouse.  Dogs, cats or monkeys present practical and ethical difficulties.  Rats have been a candidate but attempts to create a tau rat have failed.  Until now.

A team at the State University of New York at Buffalo led by Dr. Stewart D. Clark has just created a rat with something resembling PSP.  The lead author was Dr. Gabriella King.  The title of the article, in the European Journal of Neuroscience, says it all: Human wildtype tau expression in cholinergic pedunculopontine tegmental neurons is sufficient to produce PSP-like behavioural deficits and neuropathology. 

The researchers took advantage of the fact that PSP involves a complex cluster of cell bodies in the brainstem called the pedunculopontine tegmentum (PPT; often called in the literature the pedunculopontine nucleus, or PPN).  The PPT uses acetylcholine as its neurotransmitter and provides input to many other brain areas involved in PSP.  A loss of acetylcholine-based connections is a major part of the pathology of PSP.  Damage to the PPT alone causes severe gait and balance problems, and loss of its acetylcholine input to other areas causes many other symptoms.  Attempts are ongoing to develop deep-brain stimulation to the PPT as treatment for the balance problems of PSP and Parkinson’s.

The researchers started with rats that were genetically engineered to readily incorporate any introduced gene into neurons that make acetylcholine.  Then, they put the gene for normal human tau into a kind of virus that readily and safely enters brain cells – called an adeno-associated virus.  It’s a commonly-used laboratory tool.  They injected those viruses into five spots in each PPT and three in a part of each thalamus that projects to the PPT, for a total of 16 injections into each rat’s brain.

A month later, the result was gait and balance difficulties and a loss of reactivity to loud noises (which occurs to a degree in human PSP).  Autopsy showed fewer acetylcholine-making neurons in the PPT, fewer dopamine-making neurons in the substantia nigra (presumably because of a loss of input from the PPT), and abnormal aggregates of tau protein in the brainstem resembling neurofibrillary tangles.  None of these abnormalities occurred in control rats receiving injections of adeno-associated virus carrying the gene for a harmless protein into the same 16 spots.

Clearly, this model is not as convenient as the tau mouse, which can be bred in colonies without a need for 16 carefully placed brain injections.  Another problem is that rats are more expensive to purchase and maintain than mice, mostly just because they’re larger.  But for smaller-scale projects, this is a major advance.  Let’s watch for commercialization of the model and for its utilization by other labs.