The impact of ALS disease variants on regulation of heat shock protein life cycles – Implications for neuronal proteostasis
The abnormal accumulation of misfolded proteins and aggregates is the hallmark of multiple forms of ALS and other neurodegenerative diseases. The toxicity of these aberrant proteins is compounded by deficiency in mechanisms regulating protein quality control and alterations they cause in the metabolism of mRNAs that sustain neuronal functionality. A logical therapeutic strategy is to boost the production of heat shock proteins (HSPs) to act as molecular chaperones. HSPs help proteins fold into their functional conformations, target misfolded proteins for degradation, and disassociate aberrant protein complexes. Thus, they can restore protein and mRNA homeostasis. Motor neurons have a limited capacity to activate the transcription of HSPs, including the inducible HSP70 isoform, leading to the assumption that this impairment makes them vulnerable to impaired proteostasis and underlies the inefficiency of HSP-based therapies.
We have recently discovered that neurons have evolved to adapt the expression of HSPs to proteotoxic stresses through the regulation of the life cycle of constitutive HSPs, from transcription to mRNA localization and translation at neuronal projections. Remarkably, the expression of familial ALS variants of FUS and TDP43 deregulates the life cycle of HSPs and precludes the localization of their mRNAs in dendrites. Our working hypothesis is that the expression of ALS disease genes deregulates the life cycle of HSP mRNAs, debilitating the capacity of neurons to sustain protein homeostasis over their architecture and consequently compromising the efficiency of HSP-based therapies. We will capitalize on our existing tools and models to establish proof of principle, accomplishable within the resources/timeline of the ALS Discovery Grant.
Specific aims are:
AIM 1: To investigate the impact of ALS disease variants on the life cycle of HSP mRNAs, from transcription to distribution and translation to protein, in motor neurons of primary spinal cord cultures, established models of familial ALS.
AIM 2: To evaluate changes in the life cycle of motor neuron-relevant HSP mRNAs in spinal cord tissues of ALS mouse models and ultimately in ALS autopsy tissue.
AIM 3: To analyze the impact of known HSP-inducers on HSP life cycles and interference by disease mechanisms.
Experiments in this grant will help us establish principles of HSP life cycle regulation in motor neurons and their role in proteostasis, including sustaining functional interactions with other neurons. They will pave the way to define how the transcriptional, translational, and transport disturbances that are part of cellular mechanisms of disease impact HSP life cycles and the response to chaperone-based therapies that go amiss in the context of ALS.
Maria Vera Ugalde , McGill University
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