Objective:

Background:

STR expansions cause over 50 neurodegenerative diseases including cerebellar ataxias, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Despite expression of these repeats early in life, there is typically a prolonged period before symptom development in both patients and disease models. Furthermore, clinical trials aimed at silencing STRs have been successful. Improving our understanding of temporal requirements of STRs in neurodegenerative disease, including when expression is required for neurodegeneration and when silencing will be efficacious, is critical to improving future therapy development.

Design/Methods:

Here we use Drosophila models of Fragile X-associated Tremor/Ataxia Syndrome (FXTAS-trigged by CGG repeats) and C9orf72 FTD/ALS (C9 FTD/ALS-triggered by GGGGCC repeats) and the inducible GeneSwitch system to trigger silencing of repeat expansions in neurons at serial time points starting early in life and extending into adulthood while tracking a combination of survival and motor activity as readouts for neurodegeneration.

Results:

We find that in both models of FXTAS and C9 FTD/ALS, there are progressively diminishing benefits to gene silencing later in life, with a distinct “point of no return” for each repeat where gene silencing offers no further survival benefit. Additionally, a short period of expanded CGG repeat expression early in life was deleterious (rather than protective) for tolerance of re-expression later in life, further suggesting persistent consequences for early toxic events.

Conclusions:

These data support a model where early-life activation of neurodegenerative cascades trigger a compensated homeostatic state that prevents neurodegeneration. However, with aging, decompensation of this homeostatic state leads to late-life neurodegeneration that eventually becomes independent of the triggering insult after which gene silencing no longer provides benefit. Ongoing work is focused on determining the early-life compensatory homeostatic events as well as additional late-life neurodegenerative cascades.