Novel Target Identified for Treatment of ALS

Hyperphosphorylation of tau, a hallmark of Alzheimer's disease (AD), disrupts the trafficking of mitochondria across axons to synapses. This leads to axonal dysfunction, synapse loss and increased oxidative stress.

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Mitochondrial dysfunction in AD is exacerbated by abnormal interaction between hyperphosphorylated tau and dynamin-related protein 1 (DRP1), the enzyme involved in mitochondrial fission. Furthermore, tau overexpression and mislocalization increase oxidative stress in AD and other neurologic diseases.

Alterations in mitochondrial function and dynamics have also been reported in amyotrophic lateral sclerosis (ALS). Expanding on those findings, Tiziana Petrozziello, PhD, instructor in Neurology, and Ghazaleh Sadri-Vakili, MS, PhD, director of the NeuroEpigenetics Laboratory at the Institute for Neurodegenerative Disease and Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, and colleagues recently demonstrated significant mislocalization of tau to synapses, reminiscent of AD, reported in Molecular Neurobiology. What's more, the researchers found a reduction of tau to be a successful therapeutic approach in vitro.

The study evaluated the post-mortem motor cortex from 47 individuals with ALS and 25 people without neurologic disease to demonstrate the link between tau phosphorylation and mislocalization to mitochondrial dysfunction in ALS. Post-mortem motor cortex was evaluated using electron microscopy and western blots to demonstrate alterations in mitochondrial shape and function in ALS. Using cellular fractionation synapses were isolated and evaluated for tau, hyperphosphorylated tau at serine 396 (pTau-S396) and DRP1 levels.

SH-SY5Y cells were treated with a recombinant tau protein or the synaptic fraction derived from ALS post-mortem brains, enriched in pTau-S396 and DRP1, and alterations in mitochondrial morphology and function were assessed using microscopy. SH-SY5Y cells were treated with recombinant tau or the synaptic fraction derived from ALS post-mortem brains together with QC-01-175—a tau specific degrader, and mitochondrial morphology and function were assessed.

Key Findings

• Across subtypes of ALS, pTau-S396 was mislocalized to synapses
• When human neuroblastoma cells were grown in contact with pTau-S396 or synapses derived from post-mortem ALS motor cortex enriched in pTau-S396, they exhibited increases in mitochondrial fragmentation with a decrease in both length and volume as well as increased oxidative stress
• Across ALS subtypes, increases in pTau-S396 triggered pathological mitochondrial fission by interacting with DRP1
• Treatment with an investigational selective tau degrader, QC-01-175, mitigated alterations in mitochondrial length and volume, similar to the results of knocking down DRP1, and decreased levels of reactive oxygen species

Moving Towards Drug Development

Collectively, these results suggest pTau-S396 underlies mitochondrial fragmentation and oxidative stress in ALS by interacting with DRP1. Reducing pTau-S396 levels may improve mitochondrial morphology and function and in turn lengthen motor neuron survival in ALS. The team plans to investigate whether QC-01-175 is neuroprotective in animal models of ALS.

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