The mechanism by which loss of stathmin-2 induces neurodegeneration in ALS

Most of amyotrophic lateral sclerosis (ALS) and half of frontotemporal dementia (FTD) cases belong to a spectrum of disorders characterized by TAR DNA-binding protein-43 (TDP-43) proteinopathy. Further, loss of TDP-43 function–without TDP-43 inclusions–has also been associated with neuronal atrophy in both the FTD and ALS sides of the disease spectrum. Recent studies demonstrate that TDP-43 regulates the splicing of stathmin-2 (STMN2), which encodes a protein associated with microtubule dynamics. Indeed, in central nervous system (CNS) tissues from ALS/FTD patients, the aberrant accumulation of a mis-spliced STMN2 RNA and a reduction of full-length STMN2 transcripts were observed. While TDP-43 deficiency reduces full-length STMN2potentially leading to neurodegeneration in ALS/FTD, the molecular mechanisms and pathways downstream of STMN2 remain unknown. Thus, we plan to use CRISPR-inhibition (CRISPRi) system to knockdown Stmn2 in mouse CNS and elucidate the effects of Stmn2 downregulation on neurodegeneration, by evaluating behavioral deficits, and performing RNA sequencing, biochemistry and immunohistochemical analyses.