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Unravelling the mechanism(s) responsible for the therapeutic effect of histone deacetylase 6 (HDAC6) inhibition in amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterised by degeneration of the upper and lower motor neurons in the motor cortex, brainstem and spinal cord. Individuals diagnosed with ALS typically pass away within two to five years after disease diagnosis mostly due to respiratory failure. Due to the lack of available effective treatments, further research towards the development of new therapeutic interventions is necessary. Although 90% of ALS cases are sporadic, 10% are familial. The most prevalent identified mutated genes causing ALS are SOD1, TARDBP, FUS and C9orf72, whereby mutations FUS account for approximately 4% of ALS. The host lab discovered that histone deacetylase 6 (HDAC6) could be a promising therapeutic target as its inhibition ameliorates different ALS-related phenotypes in various in vitro and in vivo disease models. Thereby, it is suggested that HDAC6 plays a unique role in many biological processes linked to ALS. Even though the therapeutic potential of HDAC6 in ALS looks promising, little is known about the mechanisms underlying the observed beneficial effects of HDAC6 modulation. Therefore, the aim of this project is to elucidate the exact role of HDAC6 in ALS and to deliver mechanistic insights into the effect of HDAC6 modulation using FUS-ALS patient-derived induced pluripotent stem cell (iPSC) motor neurons alongside in vivo zebrafish models. First, I will establish in vivo whether pharmacological inhibition and transient genetic silencing of HDAC6 are able to rescue the ALS phenotype observed in the embryonic zebrafish model, expressing human FUS protein. Next, I will investigate the fundamental interactions and functions by which HDAC6 affects ALS pathogenesis in addition to unravelling its role in axonal transport, neuromuscular junction formation and stability, and ALS-associated proteotoxicity. Identifying and understanding the mechanism(s) of action underlying HDAC6 modulation will profoundly contribute to the development of a new therapeutic strategy for ALS by allowing for a more targeted approach.

Date:1 Oct 2021 →  Today
Keywords:ALS, Zebrafish, Amyotrophic lateral sclerosis, HDAC6, iPSC
Disciplines:Neurological and neuromuscular diseases
Project type:PhD project