Mechanisms of Neurodegeneration

As we age, our brains lose neurons, which cannot be replenished. When neuronal loss reaches above certain threshold, people develop devastating symptoms, such as dementia for Alzheimer’s and movement disability for Parkinson’s. There is no disease modifying therapy for these neurodegenerative diseases despite their prevalence among the elderly and enormous cost to the society.

The Shen lab takes advantage of the genetic underpinnings of Alzheimer’s and Parkinson’s to study the disease mechanisms using mice and fruit flies, genetically tractable models that share functional homologs to the human disease genes. Using a multidisciplinary approach, we discovered that the Presenilin genes, the major site of mutations that cause familial Alzheimer’s disease, play an essential role in learning and memory, synaptic function and neuronal survival, arguing against treating the disease by inhibition of Presenilin function.  Our genetic findings further showed that disease linked mutations impair Presenilin functions by reducing its enzymatic activity and lead to age-dependent neurodegeneration. We are currently looking for molecular players or pathways regulated by Presenilin that support neuronal survival during aging. Our other major research efforts use a similar approach to study why people lose most of dopamine producing neurons in the brain and develop Parkinson’s. We discovered that Parkinson’s genetic mutations converge upon two pathways, one regulating mitochondrial function and another protein degradation and turnover. Interestingly, we found that genes involved in Alzheimer’s and Parkinson’s are all required for the maintenance of normal communication between neurons in the relevant brain sub-regions affected by the disease, suggesting that they are pathogenic precursors before neuronal death.

Director Jie Shen, and Patient Advocate Michael Byrne, discuss Parkinson’s Disease research conducted at the BWH Morris K. Udall Center of Excellence for Parkinson’s Research.

Alzheimer’s Research UK (ARUK) Conference 2018, London.