The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis 2025 Friese et al

[Andy]

Highlights​

• PSMB8 is induced in neurons under inflammatory conditions, such as multiple sclerosis
• The integration of PSMB8 into the proteasome reduces proteasome activity in neurons
• This causes the accumulation of PFKFB3, triggering a metabolic switch and ferroptosis
• Targeting PSMB8 or its downstream pathways provides neuroprotection in vivo

Summary​

Inflammation, aberrant proteostasis, and energy depletion are hallmarks of neurodegenerative diseases such as multiple sclerosis (MS). However, the interplay between inflammation, proteasomal dysfunction in neurons, and its consequences for neuronal integrity remains unclear.

Using transcriptional, proteomic, and functional analyses of proteasomal subunits in inflamed neurons, we found that interferon-γ-mediated induction of the immunoproteasome subunit, proteasome 20S beta 8 (PSMB8) impairs the proteasomal balance, resulting in reduced proteasome activity. This reduction causes the accumulation of phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key metabolic regulator, leading to enhanced neuronal glycolysis, reduced pentose phosphate pathway activity, oxidative injury, and ferroptosis. Neuron-specific genetic and systemic pharmacological targeting of PSMB8 or PFKFB3 protected neurons in vitro and in a mouse model of MS.

Our findings provide a unifying explanation for proteasomal dysfunction in MS and possibly other neurodegenerative diseases, linking inflammation to metabolic disruption, and presenting an opportunity for targeted neuroprotective therapies.

Open access

 

[SNT Gatchaman]

Using transcriptional, proteomic, and functional analyses of proteasomal subunits in inflamed neurons, we found that interferon-γ-mediated induction of the immunoproteasome subunit, proteasome 20S beta 8 (PSMB8) impairs the proteasomal balance, resulting in reduced proteasome activity. This reduction causes the accumulation of phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key metabolic regulator, leading to enhanced neuronal glycolysis, reduced pentose phosphate pathway activity, oxidative injury, and ferroptosis.

Transcription Profile Analysis of Vastus Lateralis Muscle from Patients with Chronic Fatigue Syndrome (2009) found PFKFB3 to be decreased in muscle cells.

One characteristic of the CFS vastus lateralis gene profile was the depressed transcription of several genes implicated in the energy metabolism of skeletal muscle fibers. Specifically, we found that two allosteric enzymes, 6-phosphofructo2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and 6-phosphofructo-2-kinase/fructose-2,6biphosphatase I (PFKFB3), were down-regulated, suggesting that glycolysis and/or gluconeogenesis was impaired. In fact, this allosteric enzyme is bifunctional and its specific activity depends on posttrascriptional phosphorylation.

 

[jnmaciuch]

Interesting finding! I’ve bookmarked the paper for closer reading