August is for ALS

You’ve probably heard of amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig’s disease, from the Ice Bucket Challenge that blew up the Internet about four years ago. I was one of the tens of thousands nationwide who took the icy plunge to raise awareness for this debilitating condition that effects 5-7 per 100,000 people in the US. Who would’ve known a couple years later I would be working in a laboratory to find an effective treatment or better yet, a cure. As August is ALS awareness month, I thought I’d recount my experience and share what I learned. I’d also like to dedicate this article to my best friend’s grandmother who was recently diagnosed with ALS as well as her grandfather who has Alzheimer’s disease.

During my final year at Georgetown University, I interned at the Laboratory for Dementia and Parkinsonism where I delved into the pathology of ALS as well as dementia. One of the very first interesting tidbits I learned is that ALS, a motor neuron disease (MND), is now thought to be on a spectrum of the same disorder as frontotemporal dementia (FTD). More specifically, ALS is a disease of the upper and lower motor neurons that eventually leads to loss of voluntary movement, paralysis, and respiratory failure; yet, some ALS patients present with behavioral and cognitive impairment that is commonly seen in dementia. Further, a FTD diagnosis that pathologically presents with frontotemporal lobar degeneration (FTLD) can be accompanied by some degree of MND. In fact, the comorbidity of ALS and FTD is about 50%. So what’s the alleged culprit behind the neurodegeneration yielding both cognitive and motor decline?

In 2006, researchers observed specific protein fragments in post-mortem brains of ALS and FTD patients. This protein was later identified as TDP-43 (trans-activation response [TAR] DNA-binding protein of 43 kDa—I know, it’s a mouthful) and is believed to be the drive behind ALS and FTD disease progression. TDP-43 toxic protein aggregates are also observed in other neurodegenerative disorders such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Huntington’s Disease (HD). Just as alpha-synuclein is the main pathological hallmark for PD and beta-amyloid plaques and tau tangles for AD, TDP-43 aggregates are a major pathological subtype of ALS-FTD. More research is needed to investigate the role of TDP-43 in neuronal death; however, my lab hypothesized that a process called autophagy, or the disposal of cellular components, is a promising target in degrading elevated TDP-43 levels and thus reversing cognitive decline.

Autophagy is essentially the garbage disposal system in a cell, ensuring protein homeostasis and proper functioning. In fact, protein degradation mechanisms have been shown to be impaired in many neurodegenerative diseases including ALS and FTD, resulting in these toxic protein inclusions. So, it makes sense to somehow activate autophagy to prevent protein build-up and promote neuronal survival. That’s exactly what my lab did.

Recently, my lab showed that tyrosine kinase inhibitors (TKIs) or anti-cancer drugs reduce TDP-43 levels through autophagy and reverse motor and cognitive decline in MND-FTD mice. This past year, I investigated the effects of another less costly TKI and saw similar trends with the treated mice. Specifically, I saw reduced TDP-43 levels, less neuronal death, and improved behavior in the mice who received the drug. It was very exciting to say the least.

Although there is still a lot to uncover, I’m so happy I had the opportunity to contribute to this area of research and to the search for a cure for ALS and dementia.

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Elizabeth Arruda

Is a contributor to The Almost Doctor’s Channel.