Interview with Molecular Biologist and Neurologist Dr. Lorraine Kalia

Dr. Lorraine Kalia, MD, PhD, FRCPC is an assistant professor in the Division of Neurology at the University of Toronto, with appointments at the Krembil Research Institute, Tanz Centre for Research in Neurodegenerative Diseases and Department of Laboratory Medicine and Pathobiology. She is also a movement disorders neurologist in the Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s disease (PD) at Toronto Western Hospital, University Health Network. Dr. Kalia received her MD/PhD and neurology residency training at University of Toronto and conducted post-doctoral fellowships at Massachusetts General Hospital and Toronto Western Hospital. She has received research funding from the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Parkinson Canada, Parkinson’s UK and The Michael J. Fox Foundation. Her research program focuses on PD and related diseases with the goal of understanding the key molecular mechanisms responsible for neurodegeneration to develop novel therapies.    

The following has been paraphrased from an Interview with Dr. Lorraine Kalia on June 15th, 2018.

How far have we come in our understanding of the molecular mechanisms underlying Parkinson’s disease?

I think we have come a really long way. Before 1997 we didn’t even understand that alpha-synuclein was the major protein that aggregated in PD. That discovery has been pivotal to the pathological diagnosis of the disease and to our understanding of the molecular pathways involved in neurodegeneration. We have learned a lot from genetic discoveries, which I think are also going to inform our understanding of sporadic PD. Although genetic and sporadic PD may not be the same disease, similar molecular pathways are likely involved.

How far are we in understanding the non-genetic factors associated with the disease?

Genetics gives us some keys, but it is not the full picture. Because of the exciting discoveries in genetics over the past two decades, we have tended to shift our focus away from non-genetic factors such as influences from the environment. But, environmental factors definitely play a role and even influence genetics. We definitely need a greater understanding in this area.

If you compare other diseases to the diseases of the brain, do you ever fear that the complexity might be too much for us?

I look to other diseases that are further ahead as models that we can learn from. For example, cancer and immunological diseases are also complex, but that hasn’t stopped those fields from making significant therapeutic advances. Although I believe that the brain is the most complicated, sophisticated and important organ in the body, I remain optimistic that we can get to a point where we understand it well enough to intervene in neurodegenerative diseases. Similar to the brain, the immune system is a remarkably complex network in which cells need to communicate with each other for the system to function. Yet, immunology has made tremendous strides in understanding this complexity. Immune cells are easy to access (in contrast to brain cells) which has allowed that field to progress faster. However, advances in immunology demonstrate that it is possible to make sense of these incredibly complex systems.

Could you explain how monoclonal antibodies might transform our ability to tackle PD?

To fight off diseases such as infection and cancer, our immune system creates antibodies that bind to proteins on cells and label them to be destroyed by the  immune system. The rationale for using monoclonal antibodies in PD is to make antibodies that recognize alpha-synuclein and limit our amount of harmful alpha-synuclein. These antibodies are generated in a lab from identical immune cells that are clones of a single parent source, hence monoclonal. These antibodies then would be infused into people with PD. This strategy is called passive immunization. A few companies are developing these antibodies and currently they are in phase 1 and phase 2 clinical trials.

What about antisense oligonucleotides?

The alpha-synuclein gene, which is DNA, gets copied or transcribed into RNA, and then gets translated into amino acids that become the protein alpha-synuclein. What these antisense oligonucleotides do is bind to the RNA and block it from being translated into a protein, limiting the amount of that protein that gets created. Antisense oligonucleotides are being developed now for alpha-synuclein. Development of antisense oligonucleotides for Huntington’s disease is further ahead, and the initial clinical trial for Huntington’s disease has shown that this approach is safe and possible in humans.

A challenge for both antibody and antisense therapies is that we all have alpha-synuclein, and it has been estimated that 1% of the protein in our brain cells is alpha-synuclein, so it presumably is important. The hypothesis is that it takes on a form that is detrimental in PD, and the big challenge is developing a strategy in which only the harmful forms of alpha-synuclein are targeted.

Could you talk about the role of molecular chaperones and their emergence as a therapeutic target?

Our cells have evolved mechanisms to prevent harmful protein aggregation from happening. The chaperone system is one of those mechanisms. Chaperones occupy many different parts of the cell and collectively they ensure proteins are folded into their proper state. If chaperones don’t successfully get a protein to conform to their proper shape, they communicate with the autophagy and proteasomal systems in the cell to degrade the protein. Unfolded or improperly folded proteins tend to aggregate.

The best characterized chaperones are called heat shock proteins, and a variety of different stresses increase the amount of them. There is a whole family of these proteins that we are now trying to harness to improve the health of cells. But like anything, we have to be careful because there is a balance that cells maintain and if we over-express them it can have harmful effects, such as the potential to create cancerous cells.

You and your colleagues published a paper about using a combination of different alpha-synuclein models to better model this disease. How much closer has this gotten us to the human form of the disease?

The challenge with models is that they are models. We use them to expedite research and because not all research can be done with humans. There will always be drawbacks to models and they will probably never be able to perfectly match the human disease. But just because we don’t have the perfect model does not mean they can’t have some value.

If we want to better understand alpha-synuclein and develop treatments to affect alpha-synuclein, then it makes sense to use alpha-synuclein models. However, you have to know what question you want to answer with the model. If you want to understand how the spread of alpha-synuclein is regulated, or if you have a drug to test that tries to reduce its spread, then you should use a model where alpha-synuclein spreads. But if you are just curious about how alpha-synuclein leads to neurodegeneration in Parkinson’s disease, then you may want to simply use a model that over-expresses synuclein in the part of the brain relevant to the disease.

Is there any under explored avenue of research that you wish was being given more attention?

It is important to know how these proteins and molecular pathways are involved in disease but it is equally important for us to understand what they do in health. If we give people antibodies or oligonucleotides that target a protein, and we don’t know what that protein normally does, we won’t be able to safely target it. I think better understanding the role of these proteins and pathways in the brain of a person who does not have Parkinson’s might change how we think about this disease.



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