Unit 2.2: Protein Homeostasis Disruption

Protein misfolding and aggregation are common features in various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 and FUS are RNA-binding proteins that have been found to misfold and aggregate in the cytoplasm of affected neurons in these diseases, leading to cell dysfunction and death. The ubiquitin-proteasome system is responsible for protein degradation in cells, and dysfunction of this system has been implicated in the pathogenesis of ALS and FTD. When misfolded proteins like TDP-43 and FUS accumulate, they can overwhelm the proteasome and lead to further protein aggregation and cellular damage. Autophagy is another cellular process that helps to remove damaged organelles and proteins. Impairment of autophagy has been observed in motor neuron diseases (MND), including ALS, and can contribute to the accumulation of toxic protein aggregates in affected neurons. Overall, understanding the mechanisms of protein misfolding, aggregation, and clearance in neurodegenerative diseases like ALS and FTD is crucial for developing targeted therapies to slow or halt disease progression. Researchers are actively investigating ways to restore protein homeostasis and improve cellular quality control mechanisms in order to treat these devastating conditions.