While the global incidence of ALS has increased over the years, the molecular mechanisms of the disease remain largely unknown. Our innovative approach has the potential to uncover the converging mechanisms by which mutations in FUS, TDP-43 and C9orf72 result in ALS-associated protein aggregation and degeneration of motor neurons. Thus, our project can lead to novel therapeutic strategies for ALS.

Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disorder and remains incurable. Since aging is a major risk factor for the disease, the number of individuals diagnosed with ALS will rise by 69% in 2040 due to population aging. Aging is characterized by the demise of intracellular pathways that maintain cellular integrity, such as protein homeostasis (proteostasis). In ALS, motor neurons accumulate pathological protein aggregates and degenerate during aging.
To define how aging triggers ALS and diminish age as a risk factor, we proposed a series of ground-breaking approaches combining patient-derived induced pluripotent stem cells (iPSCs) with genetics in the model organism C. elegans. First, we performed an integrated analysis to identify intracellular modulators of pathological protein aggregation induced by different ALS-related mutant proteins in motor neurons derived from ALS-iPSCs. Then, we screened whether these factors modulate protein aggregation and neurotoxicity in ALS C. elegans models expressing the same human mutant variants of our ALS-iPSC lines. After we identified modulators of ALS-related protein aggregation in C. elegans models, we determined their impact in human motor neurons derived from ALS-iPSCs.
Beyond cell autonomous mechanisms, distinct tissues can influence aging of distal organs. In our previous work, we discovered that a rejuvenated germline delays the aging of neurons, opening a new perspective that needed to be explored. In this project, we have now found that a collapse in the proteostasis of C. elegans germline stem cells leads to mitochondrial alterations in neurons through long-range Wnt signaling. Subsequently, mitochondrial alterations in the nervous system increase neuronal aggregation of ALS-related proteins (Calculli et al, Science Advances 2021). Together, our project identified both cell autonomous and non-autonomous modifiers of ALS, providing potential therapeutic targets for the disease.

1. Defining changes induced by ALS-mutant related proteins

2. Screen in ALS disease models

3. Ameliorate protein aggregation in human motor neurons derived from ALS-iPSCs

David Vilchez’s laboratory has made important contributions to our understanding of how human pluripotent stem cells regulate protein quality control.

For instance, his lab found that pluripotent stem cells exhibit up-regulation of specific E3 ubiquitin ligase enzymes to modulate factors required for hESC/iPSC function and self-renewal (Saez et al, Scientific Reports 2018, Saez et al, FEBS Letters 2019). Among them, they found a novel pathway involved in the degradation and modification of histone H3 link with Huntington’s disease (Irmak et al, Human Molecular Genetics 2018, Fatima et al, In revision in Stem Cell Reports).

David’s lab also defined that the E3 ubiquitin ligase UBR5 prevents aggregation of mutant huntingtin in iPSCs derived from Huntington’s disease patients (Koyuncu et al, Nature Communications 2018). In these lines, his lab discovered that human pluripotent stem cells also have enhanced levels of other proteostasis mechanisms to suppress toxic protein aggregation (Noormohammadi et al, Nature Communications 2016). For instance, hESCs/iPSCs have endogenous mechanisms of post-transcriptional regulation and protein synthesis (Lee et al, Nature Communications 2017) as well as protein folding (Noormohammadi et al, Nature Communications 2016).

Importantly, mimicking these proteostasis mechanisms in somatic tissues was sufficient to prolong organismal healthspan and delay age-related diseases in C. elegans models (Koyuncu et al, Nature Communications 2018, Lee et al, Nature Communications 2017, Noormohammadi et al, Nature Communications 2016). Besides its work on proteostasis of stem cells, David’s laboratory has made significant advances on understanding the cell non-autonomous mechanisms by which germ stem cells regulate the fitness of the soma. Importantly, they discovered that germ stem cells communicate with somatic tissues by releasing prostaglandin signals to coordinate extended reproductive capacity with longevity under favourable conditions, without compromising either fertility or organismal healthspan (Lee et al, Nature Metabolism 2019, cover).