ALS and other TDP-43 proteinopathies
The overwhelming majority of neurodegenerative disease, referred to as ‘sporadic,’ is caused by poorly understood interactions between genetic and environmental risk factors. Due in part to the complex etiology of these diseases, broadly effective therapies are lacking. While the clinical symptoms of these disorders are heterogenous, reflecting selective neuronal death in distinct brain regions, there are pathophysiological features that link some neurodegenerative diseases. One such commonly observed pathology is the aberrant nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), which is observed in 97% of patients with amyotrophic lateral sclerosis (ALS), 50% of patients suffering from frontotemporal dementia (FTD), and approximately 50% of Alzheimer’s disease (AD) patients. Together, the neurodegenerative disorders characterized by TDP-43 pathology are referred to as ‘TDP-43 proteinopathies.’ Therapies that slow or reverse TDP-43 dysfunction thus have the potential to impact a broad group of neurogenerative disease patients; however, the mechanism by which TDP-43 mislocalization results in neuronal death is incompletely understood and potent modifiers of TDP-43 pathology are lacking.
To address these challenges, we study both the downstream consequences of TDP-43 dysfunction, as well as upstream modifiers of TDP-43 pathology. In addition to the well-known role of TDP-43 in regulating alternative splicing, we recently identified hundreds of new TDP-43 target genes regulated by alternative polyadenylation (APA). Notably, we found significant APA of MARK3, a tau kinase associated with early tau S262 phosphorylation in AD, reflecting a novel mechanistic link between TDP-43 and tau pathology that we are actively investigating further. Additionally, we discovered that noncoding genetic variants in ataxin-3 (ATXN3) represent a novel genetic risk factor for ALS. We subsequently found that ATXN3 expression substantially impacts TDP-43 pathology in human iPSC-derived neurons and in ALS/FTD patient brain tissue. We are now focused on elucidating the mechanism by which ATXN3 regulates TDP-43 while pursuing strategies to develop therapies targeting ATXN3 for the treatment of TDP-43 proteinopathies.