The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein () or repeat expansions in Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.

Tyrosine phosphorylation regulates hnRNPA2 granule protein partitioning & reduces neurodegeneration

“…Inhibition of tyrosine kinase pathways and Fyn kinase itself (Imamura et al, 2017;Kaufman et al, 2015;Nygaard, 2018;Nygaard et al, 2014;Smith et al, 2018) are potential therapeutic targets in Alzheimer's disease. Our data indicate that while tyrosine phosphorylation can reduce aggregation and phase separation in vitro, this does not clearly translate to substantial reduction of puncta formation in an in vivo model, though the toxic species is not well understood and may not be aggregates or may be smaller than the aggregates probed by fluorescence microscopy (Siddiqi et al, 2019).…”

Mitochondria, lysosomes, and dysfunction: their meaning in neurodegeneration

“…; Imamura et al . ). Furthermore, mTOR inhibition by rapamycin increases motor neurons degeneration in SOD1 G93A mouse model of ALS, while resveratrol delayed ALS onset and extended the lifespan when given to the same mouse model (Zhang et al .…”

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology

“…In this setting, the repurposing of some previously approved mechanistic anticancer drugs for ND may offer the potential to reduce both the cost and time to achieve licensed approval status. For instance, tyrosine kinase inhibitors like bosutinib [25] and masitinib [26] (which represent a standard approach for anticancer treatment) have shown promising clinical results in patients with amyotrophic lateral sclerosis and can also exert neuroprotective actions in other ND through the activation of autophagy. The search basin for anticancer drugs repositionable for neurodegeneration will ultimately require data-driven approaches grounded on specific biomarker data; such a strategy is aimed at identifying pathophysiological commonalities, potentially common molecular alterations between cancer and ND [26].…”