C3 The fine balance of proteostasis and its implications for ALS

27-11-2019

MNDA SYMPOSIUM PERTH DEC19 PRESENTATIONS

Session 2A Proteostasis/proteotoxicity

Justin J. Yerbury - University of Wollongong, Wollongong, NSW, Australia

Background: Neurodegeneration in ALS has been attributed to a variety of processes including glutamate excitotoxicity, oxidative stress, disruption of neurofilaments and axonal transport, protein aggregation, mitochondrial dysfunction, endoplasmic reticulum stress, and dysfunctional RNA metabolism and protein degradation. How these relate to the underlying mechanism or downstream consequences associated with ALS is unknown. In common with other neurodegenerative diseases such as Alzheimer’s disease, CJD, Parkinson’s disease and Huntington’s disease, there is growing evidence that protein aggregates are closely associated with degeneration in all forms of ALS.

Inclusions associated with neurodegenerative disease are made up of insoluble proteinaceous material, generally accepted to consist mainly of one main constituent, but also composed of a variety of proteins including molecular chaperones and the proteasome. Whether these inclusions or aggregates are a symptom or cause of toxicity still remains to be conclusively demonstrated.

Regardless, the answer to the question ‘what causes these inclusions?’ may uncover a deeper understanding of neuronal dysfunction in ALS. Generally speaking, protein aggregates form when protein concentration exceeds solubility. Despite this, evolution has provided proteins that live on the edge of their solubility at their functional concentration, meaning that any small changes in solubility or concentration may tip the delicate balance leading to aggregation and inclusion formation.

However, proteins are not left alone to aggregate unchecked; all cells have many complex processes that act to maintain a protein in its correct conformation, concentration and location. Therefore, a protein must evade the cells protein homeostasis systems before inclusion formation can occur. The term protein homeostasis refers to the maintenance of the proteome as a set of individual proteins in a conformation, concentration and in a location that is required for their correct function. Protein homeostasis is important in the normal ‘housekeeping’ of a cell, but becomes vital in the face of dynamic changes required for a cellular response to a given stimuli (especially important for neurones). As one would expect, the control of protein homeostasis is heavily reliant upon accurate transcription and translation. However, there are many processes in place to ensure that cellular function is not impaired.

In order to produce a fully functioning proteome the processes of transcription, RNA processing and transport, translation, protein folding, protein transport and ultimately protein degradation must be tightly regulated. Given that all genes associated with ALS can be functionally categorised into elements of protein homeostasis or its consequences we hypothesise that pertubations in this fine balancing act could cause ALS.

 

Source: Abstract Book symposium Perth

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