The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis

Abstract

Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS.

Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia

“…PFN1 was the most significantly downregulated protein. Consistent with previous findings in PFN1 C71G +/ − and M114T +/ − patient-derived lymphoblast cells 27 , 28 , all mutant PFN1 iMGs expressed lower PFN1 levels compared to control cells by Western blot analysis, with ~60% reduction in PFN1 C71G +/ − iMGs (Fig. 2b, c ) and ~30% reduction in PFN1 M114T +/ − iMGs (Fig.…”

Multi-omics integration of scRNA-seq time series data predicts new intervention points for Parkinson’s disease

“…The mutation of PFN1 (rank one) leads to the development of a neurodegenerative disease called amyotrophic lateral sclerosis 36 . PFN1 also regulates the dynamics of the actin cytoskeleton, whose dysregulation has been implicated in multiple neurodegenerative diseases such as PD and Alzheimer’s.…”

Multi-omics integration of scRNA-seq time series data predicts new intervention points for Parkinson’s disease

“…The mutation of PFN1 (rank one) leads to the development of a neurodegenerative disease called amyotrophic lateral sclerosis (Teyssou et al ., 2022). PFN1 also regulates the dynamics of the actin cytoskeleton, whose dysregulation has been implicated in multiple neurodegenerative diseases such as PD and Alzheimer’s.…”