Could antidepressants slow the march of Parkinson’s?
Parkinson’s disease (PD) is a chronic, progressive neurological condition, which is thought to affect between seven to ten million people worldwide. PD is caused by a loss of nerve cells in a region of the midbrain, the substantia nigra. This leads to a reduction in dopamine – the neurotransmitter that plays a vital role in regulating movement – which is responsible for many of the symptoms of PD including tremors, slowness of movement, changes in speech and rigid muscles.
Although there is currently no cure for PD, treatments are available to provide some relief from many of the symptoms. It is one of these treatments that ignited the interest of Dr Tim Collier, Professor of Translational Science and Molecular Medicine at Michigan State University (MSU). Excitingly, Professor Collier’s research suggests that this treatment may have a new purpose: slowing progression of PD.
Unravelling the neuroprotective effects of NOR
Nortriptyline (NOR) is an antidepressant which has been used very effectively for over 50 years to treat depression and nerve pain, symptoms commonly associated with PD. Together with collaborator Katrina Paumier, Assistant Professor of Molecular Medicine at MSU, Professor Collier noticed that NOR and other tricyclics (similar antidepressants belonging to the same class) affect neuron cell survival. The team were intrigued by the idea that these antidepressants might modify the way in which the disease progresses.
Exploring their hypothesis further, Collier and Paumier undertook retrospective analysis of clinical trial data from an early cohort of PD patients. Intriguingly, those patients who had taken tricyclic antidepressants required standard PD therapy significantly later than those who hadn’t received antidepressant medication, suggesting that the drug may well have influenced their disease progression.
The team validated their idea in animal studies. They administered the antidepressant to rats which had a toxin-induced disease that models PD. The drug had a neuroprotective effect compared to sham-administered animals: antidepressant-treated rats had significantly less neuron loss, a smaller reduction in dopamine levels and reduced motor deficit symptoms. Interestingly, their studies revealed that the protective effect was associated with increased levels of the neurotrophic factor BDNF (brain derived neurotrophic factor), which is essential for dopamine neuron survival and function. Their study sparked interest from Massachusetts researchers, Dr Peter Lansbury and Dr Craig Justman at Harvard Medical School and Lysosomal Therapeutics Inc, who showed that tricyclic antidepressants have an interesting effect on a particular protein, alpha-synuclein (α-syn).
The team were intrigued by the idea that these antidepressants might modify the way in which PD progresses
The pathology of Parkinson’s
Abundant in the human brain, α-syn is thought to have a role in dopamine release. In its normal state, α-syn exists as a single molecule, or monomer; when several α-syn monomers bind together it forms an oligomer. In PD, however, the α-syn protein becomes misfolded causing oligomers to clump together further, forming ‘fibrils’. Large build-up of these clumps, known as ‘Lewy bodies’, in neurons is in fact a hallmark sign of PD and results in neuronal cell death. Remarkably, Lansbury and Justman showed that tricyclic antidepressants slow the aggregation of α-syn in vitro. Also suspecting the involvement of α-syn, the Collier lab had already enlisted the help of MSU colleague, Dr Lapidus, who showed that NOR had potent anti-aggregation effects in another in vitro assay.
A stabilising effect
Subsequently, the team have shown that NOR is a potent inhibitor of α-syn aggregation in vivo. NOR was shown to directly bind to α-syn and stabilise its native form, preventing the formation of toxic α-syn aggregations in a rodent model of PD. This is evidence that supports the idea that progression of PD is slowed by preventing α-syn clumping. “What we’ve essentially shown is that an already FDA-approved drug that’s been studied for over 50 years and is relatively well tolerated could be a much simpler approach to treating the disease itself, not just the symptoms,” says Collier. Professor Collier is careful to note the research suggests that NOR cannot clear the pre-existing α-syn pathology which is likely present at diagnosis. Rather, he believes that the potential benefit of NOR lies with the early stages of PD, by slowing the growth of abnormal α-syn protein pathology that can build up in the brain of patients over time.
A drug that’s been studied over 50 years and is relatively well tolerated could be a much simpler approach to treating the disease itself, not just the symptoms
Undeniably, slowing the march of disease for patients with early stage PD would make it easier to live well with the disease. Extending the beneficial effects of an existing treatment that has already been approved and shown to be safe and efficacious is an exciting prospect. Professor Collier and his team are now embarking on studies in non-human primates, in conjunction with further analyses of large clinical trial data. Their aim is to further develop the case for clinical use of NOR to provide neurobiological benefit to PD patients, filling a desperately needed therapeutic gap.
During my postdoctoral training I became fascinated with the emerging field of cell transplantation as an experimental therapy. Much of this work was focused on transplanting dopamine neurons to replace those lost in Parkinson’s disease (PD). Comprehensive understanding of PD was limited and completely focused on replacing dopamine. This seemed to me at the time an ‘easy fix’ for a terrible syndrome, that I could accomplish during my career. Needless to say, with the passage of time we learned the true complexity of the problem. I never lost my passion for developing therapeutics for PD, but 30 years later, the problem remains unresolved.
To what extent do you believe that Parkinson’s is related to ageing?
An association between ageing and PD has been recognised for several decades. Ageing is the number one risk factor for developing PD. Our work demonstrates that for the dopamine neurons vulnerable to degeneration in PD, changes that occur in these neurons during ageing share important biological characteristics with the changes seen in PD. The pattern of changes we’ve examined differ not in kind, but severity, suggesting that ageing and PD exist along the same biological continuum. So, is ageing pre-PD? Yes, there is no PD without ageing, although an individual does not need to be elderly to be diagnosed with PD. Yet, even the aggressive inherited forms of PD take decades for symptoms to be expressed. And, no, ageing is not PD. The majority of individuals live out their lives without becoming parkinsonian. The biological evidence suggests that ageing actively creates a vulnerable pre-PD state that tips into PD through contributions of other genetic and environmental factors.
There is evidence suggesting that PD acts like a prion disease, like CJD. What are the similarities between the two conditions?
This question elicits heated debate among investigators, with strong opinions on both sides of the issue. Prions are proteinacious infectious particles, that are responsible for the pathology in CJD. The question is whether α-synuclein is “prion like” in producing the pathology in PD. A key aspect of this is whether pathological α-synuclein can be passed between interconnected nerve cells, over long distances and many connections, to produce the entirety of pathology in PD. Over 10 years ago, investigators in Germany and the Netherlands, proposed just such a hypothesis, based on multiple sequential connections between brain regions exhibiting pathology in PD. Ultimately, the hypothetical prion-like spread of α-synuclein was suggested to be instigated in the gut and/or nose to spread to the brain. In my view, the experimental evidence to test for this kind of spread in animal models is not convincing. But, I’m likely to be in the minority.
Your research shows that tricyclics could provide significant benefit for early PD patients but not clear existing pathology. Are there treatments in the pipeline that could help treat advanced disease?
Most experimental therapies for PD, to be effective, rely on intervention at a time when a sufficient number of neurons have not succumbed to degeneration. Once the cells are gone, they’re not coming back. This is a significant problem in late stage PD, when degeneration is at its maximum. Conceptually, the only way to address this is by physically replacing the lost cells with cell transplantation or stimulation of neurogenesis. If pathology is advanced, but a significant population of cells remain, administration of antisense oligonucleotides directed at α-synuclein shows promise. These small molecules inhibit expression of α-synuclein by its gene. In early studies, this treatment appears to both slow accumulation of pathology and clear pre-existing pathology.
What are your future plans for your research?
My immediate efforts are focused upon generating the momentum required to test NOR in a clinical trial of early PD individuals. Also, I am engaged in my collaboration with Dr Lapidus to use the combination of her test tube assay and my animal models to explore a large panel of FDA-approved drugs for agents that have anti-aggregation properties for α-synuclein. Last, but not finally, I continue to study the connection between ageing and PD, to determine whether promoting “successful” ageing will reduce the incidence of PD through interventions including lifestyle.
Professor Collier’s research explores the mechanisms of central nervous system ageing, neurodegenerative diseases and the relationship between the two. His current work is focused on the etiology of Parkinson’s disease.
National Institutes for Health (NIH)
- Dr Lisa Lapidus, Dept. Physics & Astronomy, Michigan State University
- Dr Katrina Paumier, previously MSU, now private sector
- Dr Craig Justman, Lysosomal Therapeutics Inc, Cambridge, MA
- Dr Peter Lansbury, Center for Neurologic Diseases, Harvard Medical School, Boston, MA.
Prof Collier trained at the University of Minnesota, Northwestern University and the University of Rochester, and has been a faculty member at the University of Rochester, Rush University Medical School in Chicago and the University of Cincinnati. In 2010 he was recruited to the Michigan State University College of Human Medicine where is he is E.A. Brophy Endowed Chair in Central Nervous System Disorders.
Timothy J. Collier, Ph.D. Professor,
Translational Science and Molecular Medicine
E.A. Brophy Endowed Chair in Central Nervous System Disorders
Michigan State University College of Human Medicine
400 Monroe Ave. NW
Grand Rapids, MI 49503