Imbalanced autophagy causes synaptic deficits in a human model for neurodevelopmental disorders

Area of Science:

• Neuroscience
• Epigenetics
• Cellular Biology

Background:

• Autophagy is vital for neuronal function and synaptic integrity.
• Chromatin remodeling influences autophagy, but its role in neurons is unclear.
• KANSL1 (KAT8 regulatory NSL complex subunit 1) acetylates histone H4 on lysine 16 (H4K16ac) and is linked to Koolen-de Vries Syndrome (KdVS).

Purpose of the Study:

• To investigate the role of KANSL1 in neuronal autophagy and its connection to KdVS.
• To elucidate the epigenetic mechanisms linking KANSL1 deficiency to impaired neuronal function.
• To explore potential therapeutic strategies for KANSL1-related neurodevelopmental disorders.

Main Methods:

• Utilized KANSL1-deficient human induced-pluripotent stem cells (iPSCs) from KdVS patients and genome-edited lines.
• Assessed levels of SOD1 (superoxide dismutase 1) and oxidative stress markers.
• Analyzed autophagosome accumulation, synaptic density, receptor-mediated transmission, and neuronal network activity.
• Investigated mTOR (mechanistic target of rapamycin kinase) activation and lysosome function.
• Employed pharmacological interventions to reduce oxidative stress.

Main Results:

• KANSL1 deficiency led to decreased SOD1, increased oxidative stress, and autophagosome accumulation in neurons.
• Autophagosome accumulation at excitatory synapses reduced synaptic density and AMPA receptor-mediated transmission.
• Impaired neuronal network activity was observed in KANSL1-deficient neurons.
• Increased oxidative stress promoted mTOR activation and impaired lysosome function, hindering autophagosome clearance.
• Pharmacological reduction of oxidative stress rescued autophagosome formation and restored synaptic and network activity.

Conclusions:

• KANSL1 plays a critical role in maintaining neuronal homeostasis through H4K16ac-mediated epigenetic regulation of autophagy.
• Oxidative stress is a key mediator of autophagosome accumulation and synaptic dysfunction in KANSL1 deficiency.
• Targeting oxidative stress presents a promising therapeutic avenue for KdVS and related neurodevelopmental disorders.