Research Spotlight: Durham Lab

by Brenda Shen

This month’s spotlight takes a look at a lab in the Montreal Neurological Institute focusing on motor neuron diseases and disorders of peripheral nerve. Dr. Heather Durham arrived at McGill in 1979 as a post-doctoral fellow and has made Montreal her home ever since.  

Shortly after completing her PhD in Pharmacology at the University of Alberta, Dr. Heather Durham arrived at McGill as a Postdoctoral Fellow in Toxicology. After a few years researching the neurotoxicity of insecticides, Dr. Durham transferred to Dr. Sergio Pena’s lab at the Montreal Neurological Institute where they were studying Giant Axonal Neuropathy, a childhood-onset neurological disorder. After working at the Neuro for some time, Durham was introduced to a patient at the Neuro with amyotrophic lateral sclerosis (ALS). While many are familiar with the term ALS from the viral “ice bucket challenges” that swept across social media during the summer of 2014, not many are familiar with what the disease really is. ALS is a motor neuron disease where there is a dysfunction and loss of motor neurons in the brain and spinal cord that impair muscular movement. Without stimulation, muscles begin to atrophy (degenerate) causing those with the disease to lose motor function. It begins with the movement issues that gradually transition to an inability to talk, swallow and finally breathe. After this introduction, Dr. Durham began to focus her research on ALS as she found it both scientifically and personally intriguing. Scientifically, the disease was already related to her research on neuromuscular junctions and peripheral neuropathies of motor and sensory axons, studying ALS was the natural next step in her career. Personally, Durham was personally affected by the severity of the disease and the personal strength shown by patients and families in the loss of muscle strength. At the time when Dr. Durham first began studying ALS, very little was known about the underlying mechanisms and causes of the disease. Medical genetics was still a fairly new concept and only in 1993 was the first ALS-linked gene, Superoxide Dismutase 1 (SOD1) a gene creating a mutated SOD1 protein, discovered. Durham began her ALS research working with SOD1 and using aged-in-culture motor neurons to study how introducing the SOD1 gene may cause toxicity. Throughout her research, Durham has used her cultures to uncover information on toxicity as well as evaluating the effectiveness of treatments. 25 years later, medical genetics is now a crucial aspect of ALS research with over 30 genes having been linked to the disease. An international project called Project MinE now takes place where thousands of ALS patients are having their genomes sequenced.

Currently at her lab, Dr. Durham and her associates are continuing ALS and motor neuron disease research to find therapies that can be used to help vulnerable cells defend themselves.  A major project currently taking place at the Durham Lab is enhancing the efficacy of heat shock protein inducers in motor neurons. The fact that mutant SOD1 proteins are formed in motor neurons shows that there are flaws in the proteolytic systems responsible for degrading improper proteins. Specifically, heat shock proteins (HSPs) act as molecular chaperones which handle misfolded proteins. In her research, Durham found that the proteasome, proteins which break down misfolded proteins, capacity was found significantly reduced in mice with multiple ALS types. As they continue their experimentation, the Durham lab has identified epigenetic changes (changes in gene expression) within familiar and sporadic ALS neurons. Specifically, chromatin remodeling complexes, known as nBAF complexes, were lost. Histone acetylation processes were also impaired. These issues would cause serious impairment in gene transcription. Generally, HSP expression can be upregulated by various cells when exposed to stressful conditions, this is known as a heat shock response. However, while motor neurons have high HSP expression, they are not affected by stress. In combination with the epigenetic changes in ASL, HSP expression is significantly impaired. Generally, heat shock response magnifying drugs are used as a treatment for these issues. However, these drugs are not effective in neurons. Dr. Durham and her lab are currently focusing on combining drugs used for epigenetic treatments with heat shock protein co-inducers to enhance the overall protective properties within neurons.

While the Durham lab does research on ALS, their overall focus encompasses many other motor-neuron diseases. Charcot-Marie-Tooth Disease, a hereditary condition characterized by the continuous loss of muscle tissue and touch ability across the body, is another research focus of the lab. ARSACS (Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay) is also another disease of focus that is also very relevant to lab. ARSACS is characterized by abnormal motor movements, such involuntary muscle tensing and eye movements, coordination issues, muscle wasting and difficulties with speech. What makes this disease of special interest is that most of those affected with this illness either live or have ancestors from Quebec. In fact, 1 in 1900 people in Quebec has some sort of ARSACS but in the rest of the world it is considered a rare disease.