Anand Goswami, PhD

Mutations in RNA binding proteins (RBPs) are frequent causes of familial amyotrophic lateral sclerosis (fALS) and frontotemporal dementia (FTD). The majority of these mutant RBPs, for example, Fused in Sarcoma (FUS), Tar DNA binding protein (TDP-43), and expanded hexanucleotide G4C2 repeat (C9orf72), form distinct protein aggregates in neurons and primarily affect two vital cellular mechanisms: RNA metabolism and protein quality control (PQC). Mutant RBP-mediated defects in these two mechanisms lead to further aggregations of misfolded proteins including RBPs which form a vicious cycle of defective RBP homeostasis and protein accumulation, ultimately leading to progressive neurodegeneration. Thus, understanding the mechanisms of RNA metabolism and PQC is crucial to discovering elements that can prevent, delay, and ultimately cure neurodegenerative diseases such as ALS and FTD.

Together with Dr. Neil Shneider, our laboratory aims to understand how impaired PQC (autophagy) and RBP-associated defects including transcription, splicing, nucleocytoplasmic shuttling, RBP phase-separation, and DNA damage repair (DDR) signalling, lead to progressive neurodegeneration in ALS-FTD. Using multi-disciplinary approaches including sophisticated mouse genetics along with biochemical evaluations, as well as highly innovative spatial transcriptomics, single-cell RNA sequencing, and computational approaches we are currently identifying novel pathways involving neuroprotective factors and genetic modifiers which can ameliorate disease phenotype in ALS-FTD. In addition, we complement our research translationally by utilizing tissues obtained from ALS-FTD patients, making our studies highly disease-relevant. Using the comprehensive knowledge from these studies, we will be able to develop strategies to facilitate more effective gene therapy, drug therapy, and antisense therapy for ALS-FTD and other related disorders.