RESEARCH / RQC dysfunction in neurodegeneration

The discovery of RQC was a consequence of our investigation into the molecular mechanism of neurodegeneration caused by mutation of mouse Listerin (Chu et al. 2009; Bengtson & Joazeiro 2010). We have since learned much about fundamental mechanisms of RQC. We are now using this knowledge towards a hypothesis-driven investigation of molecular mechanisms of neurodegeneration. Through these studies, we expect to gain insight into the molecular pathogenesis underlying ALS and other neurodegenerative diseases.

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RQC mutations cause abnormal gait, motor defects and neurodegeneration in mice

We had reported that mice with a mutation in Listerin manifest a neurodegenerative phenotype (Chu et al. 2009). Our subsequent finding that Listerin functions in RQC was consistent with this observation, as defects in protein quality control are a hallmark of neurodegeneration. However, it remained formally possible that the neurodegenerative phenotype resulted from a yet undiscovered, non-RQC function of Listerin. The elucidation of fundamental mechanisms of RQC provided us with tools to test these possibilities. For example, the model that defective RQC can cause neurodegeneration predicted that NEMF mutation might lead to a similar phenotype to Listerin mutation. We and our collaborators have now shown that to be indeed the case (Martin et al. 2021).

NEMF variants are strongly associated with familial neuromuscular disease in humans

To determine the relevance of our mouse findings to human disease, we have collaborated with clinicans and analyzed patients with related symptoms for sequence variants in RQC factors. The work has identified predicted detrimental mutations in human NEMF co-segregating with juvenile neuromuscular disease (Martin et al. 2021). In addition to early motor neuron disease phenotypes, 9 affected patients from 7 unrelated families displayed intellectual disability. Together, our mouse and human studies strongly point to RQC as a critical molecular pathway protecting neurons against degeneration.

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Hypothesis-driven research on molecular mechanisms of neurodegeneration

Our previous work has established a link between RQC and neurodegeneration, but exactly how LTN1 or NEMF dysfunction leads to neuronal loss remains to be understood. Addressing this problem is a major research goal of the laboratory. We are taking a hypothesis-driven approach based on the expected consequences of perturbing the system learned from mechanistic studies of RQC. Towards this goal, we are generating cellular models that are more suitable to the study of neurodegeneration mechanisms, such as iPS cell-derived neurons with CRISPR-mediated mutations in RQC components.

 

In a parallel line of work, we are interrogating the extent to which RQC activity is affected by other neurodegeneration-associated gene mutations, such as the polyglutamine-encoding expansions in the Huntington’s Disease gene, HTT. Despite the burden neurodegenerative diseases pose to patients, their families and society, their pathogenesis mechanisms remain poorly understood at the molecular level. This gap in knowledge limits, among other things, our ability to develop rational approaches for disease treatment. By tying the new knowledge on RQC to human disease, our research program aims to elucidate novel molecular mechanisms of neurodegeneration, thus helping fill the gap. Contact us for further details!