Converging disease mechanisms in amyotrophic lateral sclerosis: microRNAs and the Fragile-X protein family

• Applicants: Dr. Axel Freischmidt; Professor Francesco Roselli, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521487152

Amyotrophic lateral sclerosis (ALS) is a common (lifetime risk ~1/400) and rapidly progressing neurodegenerative disease affecting primary motoneurons of the motor cortex, brain stem and spinal cord. Associated denervation of skeletal muscles results in muscular atrophy, paralysis and death by respiratory failure. Roughly 5-10% of ALS patients report a family history of the disease (fALS) and about 2/3 thereof are explained by mutations in one of more than two dozen protein-coding ALS genes. The remaining patients are considered sporadic (sALS) with polygenic and/or environmental causality. Despite this high heterogeneity, that is also reflected in suggested pathogenic mechanisms, clinical characteristics of ALS are remarkably similar. So far, there is no effective treatment for ALS and available drugs only modestly prolong survival. Current clinical trials are restricted to few specific genetic causes and will thus be of relevance only for a small percentage of patients. Hence, better understanding convergence in ALS may help developing broader treatment strategies beneficial for most, if not all, patients. By using different and independent unbiased approaches, we and others recently implicated the Fragile-X protein (FXP) family (FMR1, FXR1 and FXR2) in ALS pathogenesis. Besides interacting with multiple ALS-related proteins and RNAs, higher FXP expression level mitigated phenotypes of different genetic ALS in vivo models, suggesting existence of converging mechanisms involving the FXPs. Most strikingly, we recently demonstrated direct interaction of the FXPs with a certain subset of microRNAs downregulated in serum and, at least partially, in motoneurons of most ALS patients independently of the underlying cause of the disease. Neuropathology of sALS and fALS patients consistently revealed aberrant expression and relation of the FXPs to pathogenic protein aggregation, a hallmark of ALS. Moreover, downregulation of FXP-binding microRNAs was already evident in pre-symptomatic carriers of causative ALS mutations long before the estimated onset of symptoms, and the FXPs are also involved in regulating the level of these microRNAs. Therefore, increasing evidence from biochemical analyses, in vivo models of ALS, as well as human data point towards converging mechanisms involving the FXPs and certain microRNAs. Consequently, in this project, we propose to explore the causes and consequences of altered FXPs and associated microRNAs in ALS. We will combine in vitro and in vivo approaches, and will focus on mechanisms regulating FXP expression and relation of the FXPs to key pathologies of ALS, namely (micro)RNA dysmetabolism, protein aggregation and synaptic integrity. Besides providing insights in converging disease mechanisms in ALS, the project is designed to identify possible novel therapeutic targets, and may be the basis for the development of treatment strategies beneficial for all ALS patients.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Andreas Hermann