Research Projects

Amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease (ND), poses a substantial burden on the aging population. ALS is clinically, genetically, and pathologically heterogeneous, primarily affecting motor neurons, leading to muscle weakness, respiratory failure, and death. On the cellular level, ALS pathologies are associated with synaptic dysfunction, axonal transport defect, neuronal loss, and biochemically, with distinct shapes, distribution, and diverse inclusions morphologies. However, the heterogeneous nature of the inclusions and their correlation with cellular dysfunctions are mainly unknown. While the abnormal aggregation of cellular proteins in inclusions, such as TDP-43, is strongly associated with sporadic ALS, familial forms are linked to mutations in over 40 genes, including TDP-43, SOD1, and Annexin A11 (ANXA11). Contradicting the conventional view of one protein forming homomeric filament in NDs, a recent breakthrough revealed the presence of heteromeric protein filaments by two functionally distinct proteins, TDP-43 and ANXA11, isolated from the NDs patient’s brain. This discovery raises a series of fundamental questions on the molecular basis of how these two proteins co-aggregate to form hybrid filaments and their mechanistic role in ALS pathology formation and other NDs. My recent work shed light on the molecular basis of the distribution of proteolytic fragments of TDP-43 aggregates on the spreading of ALS pathologies. Given the physiological evidence of TDP-43 and ANXA11 interacting for neuronal RNA transport regulation, this interaction dysregulation might bring ALS diverse pathologies and clinical heterogeneities. In this proposal, I hypothesize that the diverse shapes, morphologies, and distinct cellular localization of inclusion pathologies stem from the interaction between these proteins and may govern different biological properties, contributing to unknown disease mechanisms and clinical heterogeneity in ALS. Using diverse methodologies from protein engineering, biophysics to cell biology, my objectives will be to 1) elucidate the molecular interaction between TDP-43 and ANXA11 and identify the mechanisms leading to hybrid filament formation, 2) investigate the structural properties of hybrid and individual filaments of TDP-43 and ANXA11, 3) develop cellular models to recapitulate hybrid filament formation and diverse inclusion morphologies and 4) understand the dysregulation of physiological functions related to RNA metabolism, lysosomal transport, and cellular stability, and assess their impact on ALS pathologies. The outcome of this research will redefine our understanding of ALS pathology by unmasking novel disease mechanisms through heteromeric protein aggregation. Besides advancing fundamental insights, developing cellular models for hybrid and homomeric filaments will provide a platform for translational research, including identifying therapeutic targets and drug discovery efforts.