Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia

Abstract

No treatment for frontotemporal dementia (FTD), the second most common early-onset dementia, is available but therapeutics are being investigated to target the two main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hamstrung by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human iPSC-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease sub-types marked by TDP-43 inclusions. Lastly, we validated that truncated STMN2 RNA is elevated in the frontal cortex of a cohort of FTLD-TDP cases but not in controls or cases with progressive supranuclear palsy (PSP), a type of FTLD-tau. Further, in FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype

“…As such, the STMN2 multiallelic CA repeat is more informative than previously reported biallelic single nucleotide polymorphisms ( Landers et al, 2009 ; Blasco et al, 2011 ; Diekstra et al, 2012 ; ALSGEN, 2013 ; Lopez-Lopez et al, 2014 ; Fogh et al, 2016 ; Theunissen et al, 2020 ), and may explain disease risk in a larger population of sALS patients. As a critical neuronal maintenance factor ( Shin et al, 2014 ; Klim et al, 2019 ), attenuating STMN2 expression may be a viable therapeutic approach to modify disease in a large proportion of both fALS and sALS patients, and reinforces its potential development for use as a prognostic marker or in clinical trials for ALS ( Klim et al, 2019 ; Melamed et al, 2019 ) and other neurodegenerative diseases ( Wang et al, 2019 ; Prudencio et al, 2020 ).…”

“…Reduced STMN2 expression has been reported not only in iPSC derived motor neurons in sALS and familial ALS cases with TDP-43 pathology, but also in motor cortex and spinal motor neurons of fALS and sALS patients with C9orf72 repeat expansions, the most common inherited form of ALS ( Melamed et al, 2019 ). Additionally, reduced STMN2 expression has more recently been reported in the brain of patients with Parkinson’s disease ( Wang et al, 2019 ), and frontotemporal dementia ( Prudencio et al, 2020 ). Further supporting the finding we present here, it was also reported that levels of full length STMN2 were not always correlated to phosphorylated TDP-43 burden in patients with frontotemporal dementia ( Prudencio et al, 2020 ), suggesting that other factors outside the TDP-43/cryptic exon mechanism may contribute to regulation of STMN2 expression.…”

“…Additionally, reduced STMN2 expression has more recently been reported in the brain of patients with Parkinson’s disease ( Wang et al, 2019 ), and frontotemporal dementia ( Prudencio et al, 2020 ). Further supporting the finding we present here, it was also reported that levels of full length STMN2 were not always correlated to phosphorylated TDP-43 burden in patients with frontotemporal dementia ( Prudencio et al, 2020 ), suggesting that other factors outside the TDP-43/cryptic exon mechanism may contribute to regulation of STMN2 expression.…”

Pathogenic Genome Signatures That Damage Motor Neurons in Amyotrophic Lateral Sclerosis

“…Melamed et al proposed that ALS is associated with loss of nuclear TDP-43 [117]. Their results confirm that reduction of nuclear TDP-43 inhibits regeneration of motor axons, which is the consequence of reduction in stathmin-2 (STMN2), an essential protein for axonal growth and maintenance ( Figure 3B) [117,118].…”

Neurodegeneration in human brain organoids infected with herpes simplex virus type 1

“…Specifically, we detected downregulation of neuronal growth associated protein stathmin-2 (STMN2) and TAR DNA-binding protein 43 (TDP43/ TARDBP ) and upregulation of the non-coding RNA BC200/ BCYRN1 , which was shown to be dysregulated in AD patients’ brains (24). Expression changes of these genes are associated with AD pathogenesis (24–26).…”